SRC kinase signalling inhibitor 1 (also known as SNAP-25-interacting protein, SNIP) acts as a negative regulator of SRC by activating CSK which inhibits SRC activity and downstream signalling, leading to impaired cell spreading and migration [, ]. It regulates dendritic spine morphology []. It is involved in calcium-dependent exocytosis and may play a role in neurotransmitter release or synapse maintenance [, ].
SKAP1 (also known as SKAP55) is an immune cell-specific adaptor protein that plays an important role in T-cell adhesion, migration, and integrin clustering. It is expressed exclusively in T-lymphocytes, mast cells, and macrophages []. Binding partners include ADAP (adhesion and degranulation-promoting adaptor protein), Fyn, Riam, RapL, and RasGRP [, , ]. It contains a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1 [, ].This entry represents the SH3 domain of SKAP1.
Target of Myb1 (TOM1)-like 2 (TOM1L2) has a probable role in protein transport []. It acts as a negative regulator of growth factor-induced Src mitogenic signaling [].
UNC80 is a protein associated with the NALCN sodium channel complex, and is required for the activation of this channel by the neuropeptide substance P. NALCN activation is G-protein-independent, but requires Src kinases. NUNC80 binds Src kinases and recruits Src into the channel complex []. UNC80 is required for the proper localisation of C. elegans NCA-1 and NCA-2, the homologues of the vertebrate cation leak channel NALCN []. NCA-1 and UNC-80 regulate neuronal activity in C. elegans [].This entry represents the N-terminal domain of UNC80.
This group represents protein tyrosine phosphatase receptor type C (PTPRC)-associated protein, also known as CD45-associated protein [, ]. It is a positive regulator of PTPRC (CD45), which activates Src family kinases implicated in tumorigenesis [].
Members of this superfamily are essential for gametocytogenesis in Plasmodium falciparum. They contain a fold composed of two pseudo dyad-related repeats of the helix-turn-helix motif, serving as a platform for RNA and Src homology-3 (SH3) binding [].
Members of this family are essential for gametocytogenesis in Plasmodium falciparum. They contain a fold composed of two pseudo dyad-related repeats of the helix-turn-helix motif, serving as a platform for RNA and Src homology-3 (SH3) binding [].
HCK is a member of the Src non-receptor type tyrosine kinase (SFK) family. HCK is expressed as two isoforms, p59Hck and p61Hck, in phagocytes. It plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration [, ]. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its C-terminal tail []. This entry represents the SH2 domain of HCK.The Src non-receptor type tyrosine kinase (SFK) family members have an unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail. The SH2 domain of SFKs is involved in kinase autoinhibition and T-cell receptor signaling. The binding SH2 domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the SFKs [].
Blk is a member of the Src non-receptor type tyrosine kinase family of proteins. Blk is involved in B-cell receptor signaling and B-cell development []. Unlike most other Src members Blk lacks cysteine residues in the SH4 domain that undergo palmitylation. Blk is required for the development of IL-17-producing gamma-delta T cells []. This entry represents the SH2 domain of Blk.The Src non-receptor type tyrosine kinase (SFK) family members have an unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail. The SH2 domain of SFKs is involved in kinase autoinhibition and T-cell receptor signaling. The binding SH2 domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the SFKs [].
This entry represents receptor tyrosine-protein phosphatase (PTP) alpha (). PTP catalyses the dephosphorylation of protein tyrosine phosphate to protein tyrosine, and appear to play a pivotal role in insulin receptor signalling. It can exist as a single-pass membrane protein or in the cytoplasm. PTP-alpha is as a positive regulator of Src and Src family kinases, acting to dephosphorylate and activate Src. As such, PTP-alpha affects transformation and tumourigenesis, inhibition of proliferation and cell cycle arrest, mitotic activation of Src, integrin signalling, neuronal differentiation and outgrowth, and ion channel activity [].
This entry represents the SH2 domain found in SLAP/SLAP2.Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling. They negatively regulate T cell receptor signaling []and act as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke []. They contain adjacent Src homology 3 (SH3) and Src homology 2 (SH2) domains. SLAP has been shown to regulate receptor tyrosine kinase (RTK) signaling []. It also binds to the receptor tyrosine kinase Flt3 and plays a role in signal transduction downstream of Flt3 []. SLAP2 acts as a negative regulator of FLT3 signaling [].
This entry represents the SH3 domain of SLAP. Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling. They negatively regulate T cell receptor signaling []and act as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke []. They contain adjacent Src homology 3 (SH3) and Src homology 2 (SH2) domains. SLAP has been shown to regulate receptor tyrosine kinase (RTK) signaling []. It also binds to the receptor tyrosine kinase Flt3 and plays a role in signal transduction downstream of Flt3 []. SLAP2 acts as a negative regulator of FLT3 signaling [].
This entry represents Src-like-adapter 2 (SLAP2).Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling. They negatively regulate T cell receptor signaling []and act as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke []. They contain adjacent Src homology 3 (SH3) and Src homology 2 (SH2) domains. SLAP has been shown to regulate receptor tyrosine kinase (RTK) signaling []. It also binds to the receptor tyrosine kinase Flt3 and plays a role in signal transduction downstream of Flt3 []. SLAP2 acts as a negative regulator of FLT3 signaling [].
This entry represents SLAP.Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling. They negatively regulate T cell receptor signaling []and act as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke []. They contain adjacent Src homology 3 (SH3) and Src homology 2 (SH2) domains. SLAP has been shown to regulate receptor tyrosine kinase (RTK) signaling []. It also binds to the receptor tyrosine kinase Flt3 and plays a role in signal transduction downstream of Flt3 []. SLAP2 acts as a negative regulator of FLT3 signaling [].
Tyrosine-protein phosphatase non-receptor type 22 (PTPN22) acts as negative regulator of T-cell receptor (TCR) signalling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signalling molecules [].Variations of the PTPN22 gene affects the susceptibility of systemic lupus erythematosus (SLE) [].
TOM1-like protein 1 (TOM1L1) is an adapter protein involved in signaling pathways. It interacts with the SH2 and SH3 domains of various signaling proteins when it is phosphorylated. TOM1L1 promotes activation of Src family tyrosine kinase Fyn, possibly by disrupting intramolecular SH3-dependent interactions [].
Frk (RAK) is a member of the Src non-receptor type tyrosine kinase family of proteins. The Frk subfamily is composed of Frk/Rak and Iyk/Bsk/Gst. It is expressed primarily epithelial cells. Frk is a nuclear protein and may function during G1 and S phase of the cell cycle and suppress growth []. Unlike the other Src members it lacks a glycine at position 2 of SH4 which is important for addition of a myristic acid moiety that is involved in targeting Src PTKs to cellular membranes []. FRK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where both induce PC12 cell differentiation and beta-cell proliferation. Under conditions that cause beta-cell degeneration these proteins augment beta-cell apoptosis. The FRK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2 []. Frk has been demonstrated to interact with retinoblastoma protein []. Frk regulates PTEN protein stability by phosphorylating PTEN, which in turn prevents PTEN degradation []. Frk also plays a role in regulation of embryonal pancreatic beta cell formation [].The Src non-receptor type tyrosine kinase (SFK) family members have an unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail. The SH2 domain of SFKs is involved in kinase autoinhibition and T-cell receptor signaling. The binding SH2 domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the SFKs [].
PAG, or Cbp/PAG (Csk binding protein/phospho-protein associated with glycosphingolipid-enriched microdomains) is a transmembrane protein that has a negative regulatory role in T-cell activation through being an adapter for C-terminal Src kinase, Csk. This family of proteins is found in eukaryotes [, , , ].
TXK is a member of the Tec family, which is a group of nonreceptor tyrosine kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal cysteine-rich region. TXK forms a complex with EF-1alpha and PARP1 that regulates interferon-gamma gene transcription in Th1 cells []. This entry represents the SH3 domain of TXK.
Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR []. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5 []. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules []. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
Lck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cellsand natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling [, ]. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events []. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling []. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
HSH2D (hematopoietic SH2 domain-containing protein, also known as ALX) is an adapter protein involved in tyrosine kinase and CD28 signaling []. It is expressed exclusively in hematopoietic cells. It contains an Src homology 2 (SH2) domain, four PXXP polyproline sequences, and two likely sites of tyrosine phosphorylation. The SH2 domain plays a critical role in ALX function downstream of CD28 [].
Human immunodeficiency virus 1 (HIV-1) negative factor (Nef protein) accelerates virulent progression of acquired immunodeficiency syndrome (AIDS) by its interaction with specific cellular proteins involved in signal transduction and host cell activation. Nef has been shown to bind specifically to a subset of the Src family of kinases [].
SH3BP4 binds to the inactive Rag GTPase complex through its Src homology 3 (SH3) domain and acts as a negative regulator of amino acid-Rag GTPase-mTORC1 signaling []. It has been shown to act as an endocytic accessory protein that interacts with endocytic proteins including clathrin and dynamin, and regulates the internalization of the transferrin receptor (TfR) [].
This entry represents eukaryotic proteins that are typically between 144 and 156 amino acids in length. The entry is found in association with , . There is a conserved LGKK sequence motif. SAM/SH3 domain-containing proteins contain a Src homology 3 domain and a sterile alpha motif, suggesting that they may function as a signaling adaptor protein in lymphocytes [].
This entry represents receptor tyrosine-protein phosphatases (PTP) (), including both alpha type and epsilon type. PTP catalyses the dephosphorylation of protein tyrosine phosphate to protein tyrosine, and appear to play a pivotal role in insulin receptor signalling. It can exist as a single-pass membrane protein or in the cytoplasm. PTP-alpha is as a positive regulator of Src and Src family kinases, acting to dephosphorylate and activate Src. As such, PTP-alpha affects transformation and tumourigenesis, inhibition of proliferation and cell cycle arrest, mitotic activation of Src, integrin signalling, neuronal differentiation and outgrowth, and ion channel activity []. PTP-epsilon is a negative regulator of insulin signalling, where the cytosolic form has been shown to act in skeletal muscle []and the receptor-type enzyme has been shown to act in primary hepatocytes and liver [].
Lyn is a member of the Src non-receptor type tyrosine kinase family. It plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance [, ]. It also mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils [, , ]. Lyn plays an essential role in the transmission of signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins [, ].This entry represents the SH2 domain of Lyn.The Src non-receptor type tyrosine kinase (SFK) family members have an unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail. The SH2 domain of SFKs is involved in kinase autoinhibition and T-cell receptor signaling. The binding SH2 domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the SFKs [].
Cortactin is a key regulator of actin polymerisation in response to tyrosine kinase signalling []. It was first identified as a tyrosine-phosphorylated protein in v-Src infected fibroblasts []. It contains several domains: an N-terminal acidic (NTA) domain, a central repeat region and a C-terminal Src homology 3 (SH3) domain. The central repeat region binds to actin filaments, the NTA domain binds to the Arp2/3 complex and the SH3 domain interacts with N-WASp, Arg and WIP []. When activated, cortactin can recruit Arp2/3 complex to existing actin filaments to nucleate a new actin filament. Cortactin is involved in the regulation of cell migration, lamellipodia formation, invadopodia formation and endocytosis []. Cortactin can be phosphorylated by Src at several sites, and also binds directly to the SH2 domain of SRC. The non-receptor kinases, such as Fyn, Syk and Fer may also play a role in cortactin tyrosine phosphorylation. The structure of cortactin has been solved [].
Cytoplasmic tyrosine-protein kinase BMX (bone marrow tyrosine kinase gene on chromosome X, also known as ETK) is a non-receptor tyrosine kinase (). It plays central but diverse modulator roles in various signalling processes involved in the regulation of actin reorganisation, cell migration, cell proliferation and survival, cell adhesion, and apoptosis [, , ]. It has a role in inflammation, cardiovascular disease, and cancer []. It is activated downstream of phosphatidylinositol-3 kinase (PI3K) andthe kinase Src [].
The CAS (Crk-Associated Substrate) protein family is a group of scaffolding proteins that play important modulatory roles in both normal and pathological cell growth regulation. They contain an N-terminal Src homology 3 (SH3) domain and a substrate domain (SD). The SD contains a large number of YxxP motifs, which when phosphorylated by Src-family kinases provide canonical binding sites for proteins containing SH2 domains such as Crk, Crk-L, CRKII [].
Actin filament-associated protein 1-like 2 (AFAP1L, also known as XB130) belongs to the actin-filament associated protein (AFAP) family of adaptor proteins (including AFAP1, AFAP1L1, and AFAP1L2/XB130). XB130 is an adaptor protein for signal transduction predominantly localised in the cytoplasm, and regulates cell proliferation, survival, and gene expression []. It is a Src kinase substrate []and couples the RET/PTC oncogenic kinase to the PI 3-kinase pathway []. It is involved in growth and survival of different cancer cells [].
The SH2-containing Shc adapter proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to the Ras/mitogen-activated protein kinase (MAPK) pathway []. Three Shc genes were originally identified in mammals that encode proteins characterised by an amino-terminal phosphotyrosine binding (PTB) domain and a carboxy-terminal Src homology 2 domain. Shc1 (ShcA) is ubiquitously expressed, whereas expression of Shc2 (ShcB) and Shc3 (ShcC) appears to be limited to neuronal cells [].This entry represents Shc2.
This entry represents the SH3 domain of SH3BP4 (SH3 domain-binding protein 4). SH3BP4 binds to the inactive Rag GTPase complex through its Src homology 3 (SH3) domain and acts as a negative regulator of amino acid-Rag GTPase-mTORC1 signaling []. It has been shown to act as an endocytic accessory protein that interacts with endocytic proteins including clathrin and dynamin, and regulates the internalization of the transferrin receptor (TfR) [].
Plenty of SH3 domains protein 2 (POSH2 also known as SH3 domain-containing RING finger protein 3 or putative E3 ubiquitin-protein ligase SH3RF2) contains the Src homology 3 (SH3) domains and a RING finger domain which confers E3 ligase activity to the protein. It belongs to the POSH family, which includes POSH1, POSH2 and POSH3 []. POSH2 interacts with GTP-loaded Rac1, which is a small signaling G protein [].This entry represents the third SH3 domain of SH3RF2.
This domain is found in the C terminus of the CAS family members.The CAS (Crk-Associated Substrate) protein family is a group of scaffolding proteins that play important modulatory roles in both normal and pathological cell growth regulation. They contain an N-terminal Src homology 3 (SH3) domain and a substrate domain (SD). The SD contains a large number of YxxP motifs, which when phosphorylated by Src-family kinases provide canonical binding sites for proteins containing SH2 domains such as Crk, Crk-L, CRKII [].
PTKs catalyse the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Itk, also known as Tsk or Emt, is a member of the Tec-like subfamily of proteins, which are cytoplasmic (or nonreceptor) PTKs with similarity to Src kinases in that they contain Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Unlike Src kinases, most Tec subfamily members except Rlk also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, Itk contains the Tec homology (TH) domain containing one proline-rich region and a zinc-binding region [, ].Itk is expressed in T-cells and mast cells, and is important in their development and differentiation []. Of the three Tec kinases expressed in T-cells, Itk plays the predominant role in T-cell receptor (TCR) signalling. It is activated by phosphorylation upon TCR crosslinking and is involved in the pathway resulting in phospholipase C-gamma1 activation and actin polymerization []. It also plays a role in the downstream signalling of the T-cell costimulatory receptor CD28, the T-cell surface receptor CD2, and the chemokine receptor CXCR4 [, ]. In addition, Itk is crucial for the development of T-helper(Th)2 effector responses [].
Fyn and Yrk (Yes-related kinase) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Fyn, together with Lck, plays a critical role in T-cell signal transduction by phosphorylating ITAM (immunoreceptor tyr activation motif) sequences on T-cell receptors, ultimately leading to the proliferation and differentiation of T-cells []. In addition, Fyn is involved in the myelination of neurons, and is implicated in Alzheimer's []and Parkinson's diseases []. Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury [].Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
PACSIN2 (protein kinase C and casein kinase substrate in neurons protein 2, also known as Syndapin-2) belongs to the PACSIN family that contains a N-terminal F-BAR (FCH-BAR) domain and a C-terminal SH3 domain []. They are cytoplasmic phosphoproteins that play a role in vesicle formation andtransport []. PACSIN2 interacts with several proteins such as Rac1, dynamin, Neuronal Wiskott-Aldrich Syndrome Protein (N-WASP), and synaptojanin via its C-terminal Src homology 3 (SH3) domain []. PACSIN2 negatively regulates the EGF (epidermal growth factor) receptor activation and signaling [, ]. It plays an important role in caveolae membrane sculpting [].
Mucin-16 (also known as CA125) belongs to the mucin family. They are high molecular weight proteins that are components of mucus and are synthesised and secreted by specialised cells of the epithelium (goblet cells, cells of mucous glands) or non mucin-secreting cells []. Mucin-16 is over-expressed in human epithelial tumors including ovarian, breast and digestive tract carcinomas [, ]. Its expression is an independent predictor of poor outcome in pancreatic ductal adenocarcinomas and probably in esophageal adenocarcinomas and gastric adenocarcinomas, being proposed to be used as a prognostic marker and a therapeutic target []. It interacts with Src family kinases (SFKs) and this may affect cell-cell adhesion of epithelial cancer cells [].
Breast cancer anti-estrogen resistance protein 1 (BCAR1, also known as p130Cas) is a member of the Cas (Crk-associated substrate) family of adaptor proteins, which function as key signalling nodes with important regulatory roles in normal and pathological cells [, ]. BCAR1 plays a central coordinating role for tyrosine kinase-based signalling through focal adhesion kinase (FAK) []. It is readily phosphorylated by FAK and Src []. Overexpression of BCAR1 confers anti-estrogen resistance on breast cancer cells []. It regulates the tumour suppressor function of TGF-beta during breast cancer progression through regulation of Smad2/3 activity [].
Cytoplasmic tyrosine-protein kinase BMX (bone marrow tyrosine kinase gene on chromosome X, also known as ETK) is a non-receptor tyrosine kinase (). It plays central but diverse modulator roles in various signalling processes involved in the regulation of actin reorganisation, cell migration, cell proliferation and survival, cell adhesion, and apoptosis [, , ]. It has a role in inflammation, cardiovascular disease, and cancer []. It is activated downstream of phosphatidylinositol-3 kinase (PI3K) and the kinase Src [].This entry represents the SH2 domain of BMX.
Tyrosine-protein kinase Fgr belongs to the SRC family of the Tyr protein kinases. It is a non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors devoid of kinase activity and contributes to the regulation of immune responses, including neutrophil, monocyte, macrophage and mast cell functions, cytoskeleton remodeling in response to extracellular stimuli, phagocytosis, cell adhesion and migration [, , ]. It contains a protein kinase domain, an SH2 domain and an SH3 domain. Fgr interacts with tyrosine phosphorylated SYK, FLT3 and HCLS1 via its SH2 domain [].This entry represents the SH2 domain of Fgr.
This entry represents the C-terminal domain of protein UNC80 from eukaryotes, a component of the NALCN sodium channel complex. NALC is a cation voltage-independent channel activated by substance P, neurotensin, acetylcholine and noradrenaline that controls neuronal excitability. UNC80 forms a complex with UNC79 and both are key regulators of the channel and required for the proper expression and axonal localisation of NALCN. UNC80 is required for NALCN control by GPCRs and essential for its sensitivity to extracellular calcium. This protein acts as a scaffold for Src family of tyrosine kinases (SFK) and UNC-79 to mediate interaction with NALCN [, , ].
The SH2-containing Shc adapter proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to the Ras/mitogen-activated protein kinase (MAPK) pathway []. Three Shc genes were originally identified in mammals that encode proteins characterised by an amino-terminal phosphotyrosine binding (PTB) domain and a carboxy-terminal Src homology 2 domain. Shc1 (ShcA) is ubiquitously expressed, whereas expression of Shc2 (ShcB) and Shc3 (ShcC) appears to be limited to neuronal cells [].Shc3 (also known as NShc from neuronal Shc) mediates neurotrophin and other neuronal signallings in the central nervous system [, ].
Otoraplin, also known as MIAL (MIA-like), is specifically expressed in the cochlea and the vestibule of the inner ear and may contribute to inner ear dysfunction in humans []. It is a member of the MIA family. MIA (melanoma inhibitory activity) family members include MIA, MIAL, MIA2, and MIA3 (also called TANGO). MIA was found to be strongly expressed and secreted by malignant melanomas. It contains a domain that adopts a Src Homology 3 (SH3) domain-like fold; however, it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. Unlike classical SH3 domains, MIA does not bind proline-rich ligands [, ].
Human immunodeficiency virus 1 (HIV-1) negative factor (Nef protein) accelerates virulent progression of acquired immunodeficiency syndrome (AIDS) by its interaction with specific cellular proteins involved in signal transduction and host cell activation. Nef has been shown to bind specifically to a subset of the Src family of kinases [].Negative factor (Nef) has a two-domain structure consisting of an N-terminal anchor domain and a core domain separated by a specific cleavage site of the HIV proteases. The N-terminal domain is not compactly folded and constitutes a mobile membrane anchor and a linker to the core domain [, ].
Human immunodeficiency virus 1 (HIV-1) negative factor (Nef protein) accelerates virulent progression of acquired immunodeficiency syndrome (AIDS) by its interaction with specific cellular proteins involved in signal transduction and host cell activation. Nef has been shown to bind specifically to a subset of the Src family of kinases [].Negative factor (Nef) has a two-domain structure consisting of an N-terminal anchor domain and a core domain separated by a specific cleavage site of the HIV proteases. The N-terminal domain is not compactly folded and constitutes a mobile membrane anchor and a linker to the core domain [, ].
Coronins belong to the WD40-repeat family, which contains the WD40 motifs that act as the protein-protein interaction sites. There are several isoforms of Coronin in mammalian cells []. This entry represents Coronin 7. Unlike most of the Coronin isoforms, Coronin 7 has not been shown to interact with actin []. Instead, Coronin 7 binds to the outer side of Golgi complex membranes and acts as a mediator of cargo vesicle formation at the trans-Golgi network []. It physically interacts with both the AP-1 adaptor protein complex and the Src kinase [].
Protein diaphanous homologue 3 (DIAPH3) belongs to the formin homology family, Diaphanous subfamily (also known as the Diaphanous-related formins, Drfs). In addition to the FH1 and FH2 domains, Drfs contain an N-terminal GTPase-binding domain (mDiaN) and a C-terminal Diaphanous-autoregulatory domain (DAD).DIAPH3 (also known as mDia2, which can be confusing) acts in a Rho-dependent manner to recruit profilin to the membrane, where it promotes actin polymerisation. It is required for cytokinesis, stress fibre formation, and transcriptional activation of the serum response factor []. It couples Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics [].
This entry represents the third SH3 domain of SH3PXD2A. Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells [, ]. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion []. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains.
This entry represents the first SH3 domain of SH3PXD2A. Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells [, ]. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion []. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains.
This entry represents the second SH3 domain of SH3PXD2A. Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells [, ]. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion []. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains.
This entry represents the fourth SH3 domain of SH3PXD2A. Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells [, ]. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion []. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains.
This entry represents the fifth SH3 domain of SH3PXD2A. Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells [, ]. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion []. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains.
Otoraplin, also known as MIAL (MIA-like), is specifically expressed in the cochlea and the vestibule of the inner ear and may contribute to inner ear dysfunction in humans []. It is a member of the MIA family. MIA (melanoma inhibitory activity) family members include MIA, MIAL, MIA2, and MIA3 (also called TANGO). MIA was found to be strongly expressed and secreted by malignant melanomas. It contains a domain that adopts a Src Homology 3 (SH3) domain-like fold; however, it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. Unlike classical SH3 domains, MIA does not bind proline-rich ligands [, ].
Breast cancer anti-estrogen resistance protein 1 (BCAR1, also known as p130Cas) is a member of the Cas (Crk-associated substrate) family of adaptor proteins, which function as key signalling nodes with important regulatory roles in normal and pathological cells [, ]. BCAR1 plays a central coordinating role for tyrosine kinase-based signalling through focal adhesion kinase (FAK) []. It is readily phosphorylated by FAK and Src []. Overexpression of BCAR1 confers anti-estrogen resistance on breast cancer cells []. It regulates the tumour suppressor function of TGF-beta during breast cancer progression through regulation of Smad2/3 activity [].This entry represents the SH3 domain of BCAR1.
Yes kinase (also known as c-Yes) is a member of the Src family of nonreceptor tyrosine kinases []. It is involved in the regulation of cell division, differentiation, survival, motility, adhesion, spreading and vesicular transport []. It plays an important role in epiboly during early development in zebrafish []. Yes kinase contains an SH4 motif responsible for membrane localization, a Unique domain, followed by SH3 and SH2 domains, the protein tyrosine kinases or SH1 domain, and a carboxy terminal regulatory region []. This entry represents the SH3 domain of Yes tyrosine kinase.
CASS4, also known as HEPL, is a Cas family member that regulates FAK and cell spreading [].The CAS (Crk-Associated Substrate) protein family is a group of scaffolding proteins that play important modulatory roles in both normal and pathological cell growth regulation. They contain an N-terminal Src homology 3 (SH3) domain and a substrate domain (SD). The SD contains a large number of YxxP motifs, which when phosphorylated by Src-family kinases provide canonical binding sites for proteins containing SH2 domains such as Crk, Crk-L, CRKII [].
This entry represents the central region of protein UNC80 from eukaryotes, a component of the NALCN sodium channel complex. NALCN is a cation voltage-independent channel activated by substance P, neurotensin, acetylcholine and noradrenaline that controls neuronal excitability. UNC80 forms a complex with UNC79 and both are key regulators of the channel and required for the proper expression and axonal localisation of NALCN. UNC80 is required for NALCN control by GPCRs and essential for its sensitivity to extracellular calcium. This protein acts as a scaffold for Src family of tyrosine kinases (SFK) and UNC-79 to mediate interaction with NALCN [, , ]. Proteins containing this domain also include some uncharacterised proteins from fungi.
Lck is a member of the Src non-receptor type tyrosine kinase family of proteins. CD4 and CD8 directly couple with Lck, and cross-linking of these receptors leads to Lck activation [, ]. The N-terminal tail of Lck is myristoylated and palmitoylated and it tethers the protein to the plasma membrane of the cell. Lck also contains an SH3 domain, an SH2 domain, and a C-terminal tyrosine kinase domain. Lck has 2 phosphorylation sites, the first an autophosphorylation site that is linked to activation of the protein and the second which is phosphorylated by Csk, which inhibits it. Lck is also inhibited by SHP-1 dephosphorylation and by Cbl ubiquitin ligase, which is part of the ubiquitin-mediated pathway []. This entry represents the SH2 domain of Lck.The Src non-receptor type tyrosine kinase (SFK) family members have an unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail. The SH2 domain of SFKs is involved in kinase autoinhibition and T-cell receptor signaling. The binding SH2 domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the SFKs [].
Btk (Bruton tyrosine kinase) is a member of the Tec family, which is a group of nonreceptor tyrosine kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Btk also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain with proline-rich and zinc-binding regions [].Btk is expressed in B-cells, and a variety of myeloid cells including mast cells, platelets, neutrophils, and dendrictic cells [, ]. It interacts with a variety of partners, from cytosolic proteins to nuclear transcription factors, suggesting a diversity of functions. Stimulation of a diverse array of cell surface receptors, including antigen engagement of the B-cell receptor (BCR), leads to PH-mediated membrane translocation of Btk and subsequent phosphorylation by Src kinase and activation []. Btk plays an important role in the life cycle of B-cells including their development, differentiation, proliferation, survival, and apoptosis []. Mutations in Btk cause the primary immunodeficiency disease, X-linked agammaglobulinaemia (XLA) in humans [, ]. This entry represents the SH3 domain of Btk.
Melanoma-derived growth regulatory protein or Melanoma inhibitory activity (MIA) is a 12kDa protein that is secreted from both chondrocytes and malignant melanoma cells. It has effects on cell growth and adhesion and it may play a role in melanoma metastasis and cartilage development. MIA elicits growth inhibition on melanoma cells in vitro. It is possible that secretion of MIA in vivo leads to decreased adhesiveness of melanocytic cells and thereby promotes melanoma progression and invasion []. Crystal structure revealed an Src homology 3 (SH)-like domain with N- and C-terminal extensions of about 20 aa each. It is thefirst structure of a secreted protein that contains an SH3 subdomain. MIA SH3 subdomain shares sequence similarity with canonical SH3 domains, suggesting that they are evolutionary related. It has a protein interaction site and, unlike conventional SH3 domains, MIA does not recognise polyproline helices [].
The function of the malignant brain tumor (MBT) repeat is unknown, but is found in a number of nuclear proteins involved in transcriptional repression. The repeat contains a completelyconserved glutamate at its amino terminus that may be important for function.The crystal structure of the two MBT repeats of human SCM-like 2 protein has been reported. Each repeat consists of an extended "arm"and a globular core. The arm of the first repeat packs against the core of the second repeat and vice versa. The structure of the core-interacting part of each arm consists of an N-terminal α-helix and a turn of 310helix connected by a short β-strand. The core consists of an Src homology 3-like five-stranded β-barrel followed by a C-terminal α-helix and another short β-strand. Each arm interacts with its partner core in a similar way, with the orientation of the N-terminal helix relative to the barrel varying slightly. There are also extensive interactions between the two barrels [].
This is a Src homology-3 (SH3) like β-barrel domain which can be found in Dda enzyme. Dda is a phage T4 SF1B helicase. The Dda SH3 domain contains two insertions (compared to RecD2), a second β-ribbon that is referred to as the hook and a β-ribbon/two-helix substructure that is referred to as the tower. The tower region within the domain is rigidly connected to domain 2A in Dda and appears to be specifically designed for the task of supporting the extended pin. Hence, it is suggested that 2A and this SH3 domain move as one unit during the ATP-driven translocation of ssDNA while maintaining contact with the pin. In this scenario, the pin-tower interaction can be considered as an additional transmission site that serves to more efficiently couple the energy from ATP binding and hydrolysis to the unwinding of dsDNA [].
This entry represents the core domain of the ferrous iron (Fe2+) transport protein FeoA found in bacteria. This domain also occurs at the C terminus in the diphtheria toxin repressor (DtxR). DtxR is a iron-binding repressor that contains two domains separated by a short linker. The C-terminal domain adopts a fold similar to eukaryotic Src homology 3 domains, but its functional role is unknown [].The transporter Feo is composed of three proteins: FeoA a small, soluble SH3-domain protein probably located in the cytosol; FeoB, a large protein with a cytosolic N-terminal G-protein domain and a C-terminal integral inner-membrane domain containing two 'Gate' motifs which likely functions as the Fe2+ permease; and FeoC, a small protein apparently functioning as an [Fe-S]-dependent transcriptional repressor [, ]. Feo allows the bacterial cell to acquire iron from its environment.
This entry represents the SH2 domain found in Drosophila shark protein and hydra protein HTK16. Shark and HTK16 are non-receptor protein-tyrosine kinases contain two SH2 domains, five ankyrin (ANK)-like repeats, and a potential tyrosine phosphorylation site in the carboxyl-terminal tail which resembles the phosphorylation site in members of the src family. Like, mammalian non-receptor protein-tyrosine kinases, ZAP-70 and syk proteins, they do not have SH3 domains. However, the presence of ANK makes these unique among protein-tyrosine kinases. Both tyrosine kinases and ANK repeats have been shown to transduce developmental signals, and SH2 domains are known to participate intimately in tyrosine kinase signaling [].Drosophila Shark transduces intracellularly the Crumbs, a protein necessary for proper organization of ectodermal epithelia, intercellular signal []. It is essential for Draper-mediated signalling [].
Actin filament-associated protein 1 (AFAP1, also known as AFAP-110) belongs to the actin-filament associated protein (AFAP) family of adaptor proteins (including AFAP1, AFAP1L1, and AFAP1L2/XB130). AFAP1 functions as an adaptor protein, linking Src kinases and/or other signalling proteins to actin filaments. It can cross-link actin filaments into both network and bundle structures []. AFAP1 contains several protein binding modules, including two pleckstrin homology domains (PH domains), a leucine zipper motif and a target sequence for serine/threonine phosphorylation []. It interacts with actin filaments directly via an actin-binding domain (ABD) located in its C terminus, and through this interaction is involved in the regulation of the cytoskeletal structure []. Its overexpression has been linked to cancers [, ].
This entry represents the PX domain found in Rho GTPase-activating protein 32 (ARHGAP32, also known as RICS). RICS is a Rho GTPase-activating protein for cdc42 and Rac1. It is implicated in the regulation of postsynaptic signaling and neurite outgrowth. An N-terminal splicing variant of RICS containing additional PX and Src Homology 3 (SH3) domains, also called PX-RICS, is the main isoform expressed during neural development. PX-RICS is involved in neural functions including axon and dendrite extension, postnatal remodeling, and fine-tuning of neural circuits during early brain development []. The PX domain is involved in targeting of proteins to PI-enriched membranes, and may also be involved in protein-protein interaction []. The PX domain of PX-RICS specifically binds phosphatidylinositol 3-phosphate (PI3P), PI4P, and PI5P [].
This family consists of several eukaryotic SH3 domain-binding protein 5 or c-Jun N-terminal kinase (JNK)-interacting proteins (SH3BP5 or Sab). Sab binds to and serves as a substrate for JNK in vitro, and has been found to interact with the Src homology 3 (SH3) domain of Bruton's tyrosine kinase (Btk). Inspection of the sequence of Sab reveals the presence of two putative mitogen-activated protein kinase interaction motifs (KIMs) similar to that found in the JNK docking domain of the c-Jun transcription factor, and four potential serine-proline JNK phosphorylation sites in the C-terminal half of the molecule [].This entry also includes REI-1 and REI-2 from C. elegans. REI-1 is a guanine nucleotide exchange factors (GEFs) for RAB-11. It functions in early embryos [].
Protein diaphanous homologue 1 (Dia1) belongs to the formin homology family, Diaphanous subfamily (also known as the Diaphanous-related formins, Drfs). In addition to the FH1 and FH2 domains, Drfs contain an N-terminal GTPase-binding domain (mDiaN) and a C-terminal Diaphanous-autoregulatory domain (DAD).Dia1 contains the N-terminal RhoA-binding domain (RBD) followed by a four armadillo-repeats containing Diaphanous inhibitory domain (DID) that binds the C-terminal Diaphanous autoregulatory domain (DAD) [, ]. Dia1 nucleates actin filaments and regulate actin polymerisation and depolymerisation. The activities of Dia1 is regulated by an autoinhibitory interaction between DAD domain and the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments []. Dia1 couples Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics [].
MIA2 is expressed specifically in hepatocytes and its expression is controlled by hepatocyte nuclear factor 1 binding sites in the MIA2 promoter [, ]. It inhibits the growth and invasion of hepatocellular carcinomas (HCC) and may act as a tumour suppressor []. A mutation in MIA2 in mice resulted in reduced cholesterol and triglycerides. Since MIA2 localizes to ER exit sites, it may function as an ER-to-Golgi trafficking protein that regulates lipid metabolism []. MIA2 contains an N-terminal SH3-like domain, similar to MIA.MIA (melanoma inhibitory activity) family members include MIA, MIAL, MIA2, and MIA3 (also called TANGO). MIA was found to be strongly expressed and secreted by malignant melanomas. It contains a domain that adopts a Src Homology 3 (SH3) domain-like fold; however, it contains an additional antiparallel beta sheet and two disulfide bonds compared to classical SH3 domains. Unlike classical SH3 domains, MIA does not bind proline-rich ligands [, ].
This entry represent the first SH3 domain of Nck2. It binds the PxxDY sequence in the CD3e cytoplasmic tail; this binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression []. Nck2 (also known as Grb4) is a member of the Nck family. It plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling []. It binds neuronal signaling proteins such as ephrinB []. Cytoplasmic proteins Nck are non-enzymatic adaptor proteins composed of three SH3 (Src homology 3) domains and a C-terminal SH2 domain []. They regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates []. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics []. They associate with tyrosine-phosphorylated growth factor receptors or their cellular substrates [, ]. There are two vertebrate Nck proteins, Nck1 and Nck2.
This entry represents the SH3 domain of Tec [, ]. Tec is a cytoplasmic (or nonreceptor) tyrosine kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain []. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions []. It is more widely-expressed than other Tec subfamily kinases. Tec is found in endothelial cells, both B- and T-cells, and a variety of myeloid cells including mast cells, erythroid cells, platelets, macrophages and neutrophils [, ]. Tec is a key component of T-cell receptor (TCR) signaling, and is important in TCR-stimulated proliferation and phospholipase C-gamma1 activation [].
Cortactin was originally identified as a substrate of Src kinase []. It is an actin regulatory protein that binds to the Arp2/3 complex and stabilizes branched actin filaments [, ]. It is involved in cellular processes that affect cell motility, adhesion, migration, endocytosis, and invasion [, , , ]. Cortactin contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain []. The N-terminal region interacts with the Arp2/3 complex and F-actin, and is crucial in regulating branched actin assembly []. Cortactin also serves as a scaffold and provides a bridge to the actin cytoskeleton for membrane trafficking and signaling proteins that bind to its SH3 domain. Binding partners for the SH3 domain of cortactin include dynamin2, N-WASp, MIM, FGD1, among others []. This entry represents the SH3 domain of cortactin.
Enhancer of filamentation 1 (also known as NEDD9 or Cas-L) is a member of the CAS family. It is a scaffolding protein that assembles signaling complexes regulating multiple cellular processes, such as cell adhesion, migration, invasion, and metastasis. It is commonly dysregulated during cancer progression. It interacts with Aurora-A kinase to control ciliary resorption, and with Src and other partners to influence proliferative signaling pathways often activated in autosomal dominant polycystic kidney disease [].CAS (Crk-associated substrate) family members are adaptor proteins that contain a highly conserved N-terminal SH3 domain, an adjacent unstructured domain (substrate domain) containing multiple tyrosine phosphorylation sites that enable binding by SH2-domain containing proteins, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. Most of these domains mediate protein-protein interactions. Through these interactions, they assemble larger signaling complexes that are essential for cell proliferation, survival, migration, and other processes []. The CAS family consists of four members: BCAR1, HEF1, EFS, and CASS4 [].
PACSIN2 (protein kinase C and casein kinase substrate in neurons protein 2, also known as Syndapin-2) belongs to the PACSIN family that contains a N-terminal F-BAR (FCH-BAR) domain and a C-terminal SH3 domain []. They are cytoplasmic phosphoproteins that play a role in vesicle formation and transport []. PACSIN2 interacts with several proteins such as Rac1, dynamin, Neuronal Wiskott-Aldrich Syndrome Protein (N-WASP), and synaptojanin via its C-terminal Src homology 3 (SH3) domain []. PACSIN2 negatively regulates the EGF (epidermal growth factor) receptor activation and signaling [, ]. It plays an important role in caveolae membrane sculpting []. This entry represents the F-BAR domain of PACSIN2. F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization [].
Palladin is a cytoskeletal actin scaffold protein that regulates actin dynamics. The immunoglobulin-like domain of palladin is directly responsible for both actin binding and bundling [, ]. Palladin also interacts with different actin binding proteins and signalling intermediaries required for regulation of cytoskeleton organisation, including profilin [], VASP [], Eps8 [], ezrin [], Lasp-1 [], and Src []. Palladin plays an important role in smooth and skeletal muscle differentiation [, , ], contraction []and cell migration [, , ].Palladin is expressed as several alternatively spliced isoforms, having various combinations of Ig-like domains, in a cell-type-specific manner. It has been suggested that palladin's different Ig-like domains may be specialized for distinct functions []. This entry represents the C-terminal immunoglobulin-like domain (Ig5).
PRLR is a receptor for the anterior pituitary hormone prolactin (PRL) [, ]. PRL participates in a variety of physiological processes in vertebrates, including reproduction, osmo-regulation, growth and development, metabolism, immuno-regulation, energy balance, and behavior []. Upon ligand binding of PRL to PRLR, the Janus-activated kinase 2 (JAK2) is activated, which in turn initiates intracellular signalling cascades, including signal transducers and activators of transcription (STAT) family members STAT-1/3/5, and extracellular regulated kinases (ERK1/2) and AKT []. PRLR also acts as a prosurvival factor for spermatozoa by inhibiting sperm capacitation through suppression of SRC kinase activation and stimulation of AKT [].Mutations in the PRLR gene cause multiple fibroadenomas of the breast (MFAB) []and hyperprolactinemia (HPRL) [].
The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps []. Similar sequences were later found in many other intracellular signal-transducing proteins []. SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific, SH2 domains recognise between 3-6 residues C-terminal to the phosphorylated tyrosine in a fashion that differs from one SH2 domain to another, and strictly phosphorylation-dependent manner [, , , ]. They are found in a wide variety of protein contexts e.g., in association with catalytic domains of phospholipase Cy (PLCy) and the non-receptor protein tyrosine kinases; within structural proteins such as fodrin and tensin; and in a group of small adaptor molecules, i.e Crk and Nck. The domains are frequently found as repeats in a single protein sequence and will then often bind both mono- and di-phosphorylated substrates. The structure of the SH2 domain belongs to the α+β class, its overall shape forming a compact flattened hemisphere. The core structural elements comprise a central hydrophobic anti-parallel β-sheet, flanked by 2 short α-helices. The loop between strands 2 and 3 provides many of the binding interactions with the phosphate group of its phosphopeptide ligand, and is hence designated the phosphate binding loop, the phosphorylated ligand binds perpendicular to the β-sheet and typically interacts with the phosphate binding loop and a hydrophobic binding pocket that interacts with a pY+3 side chain. The N- and C-termini of the domain are close together in space and on the opposite face from the phosphopeptide binding surface and it has been speculated that this has facilitated their integration into surface-exposed regions of host proteins [].
The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps []. Similar sequences were later found in many other intracellular signal-transducing proteins []. SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific, SH2 domains recognise between 3-6 residues C-terminal to the phosphorylated tyrosine in a fashion that differs from one SH2 domain to another, and strictly phosphorylation-dependent manner [, , , ]. They are found in a wide variety of protein contexts e.g., in association with catalytic domains of phospholipase Cy (PLCy) and the non-receptor protein tyrosine kinases; within structural proteins such as fodrin and tensin; and in a group of small adaptor molecules, i.e Crk and Nck. The domains are frequently found as repeats in a single protein sequence and will then often bind both mono- and di-phosphorylated substrates. The structure of the SH2 domain belongs to the α+β class, its overall shape forming a compact flattened hemisphere. The core structural elements comprise a central hydrophobic anti-parallel β-sheet, flanked by 2 short α-helices. The loop between strands 2 and 3 provides many of the binding interactions with the phosphate group of its phosphopeptide ligand, and is hence designated the phosphate binding loop, the phosphorylated ligand binds perpendicular to the β-sheet and typically interacts with the phosphate binding loop and a hydrophobic binding pocket that interacts with a pY+3 side chain. The N- and C-termini of the domain are close together in space and on the opposite face from the phosphopeptide binding surface and it has been speculated that this has facilitated their integration into surface-exposed regions of host proteins [].
Amphiphysins belong to the expanding BAR (Bin-Amphiphysin-Rvsp) family proteins, all members of which share a highly conserved N-terminal BAR domain, which has predicted coiled-coil structures required for amphiphysin dimerisation and plasma membrane interaction []. Almost all members also share a conserved C-terminal Src homology 3 (SH3) domain, which mediates their interactions with the GTPase dynamin and the inositol-5'-phosphatase synaptojanin 1 in vertebrates and with actin in yeast. The central region of all these proteins is most variable. In mammals, the central region of amphiphysin I and amphiphysin IIa contains a proline-arginine-rich region for endophilin binding and a CLAP domain, for binding to clathrin and AP-2. The interactions mediated by both the central and C-terminal domains arebelieved to be modulated by protein phosphorylation [, ].Amphiphysins are proteins that are thought to be involved in clathrin-mediated endocytosis, actin function, and signalling pathways. In vertebrates, amphiphysins may regulate, but are not essential for clathrin-mediated endocytosis of SVs. However, in Drosophila amphiphysin is not involved at all in SV endocytosis but is required for T-tubule structure and excitation-contraction coupling muscles and plays a role in membrane morphogenesis in developing photoreceptors and a variety of other cells [].
Signal transduction by T and B cell antigen receptors and certain receptorsfor Ig Fc regions involves a conserved sequence motif, termed animmunoreceptor tyrosine-based activation motif (ITAM). It is also found in thecytoplasmic domain of the apoptosis receptor. Phosphorylation of the two ITAMtyrosines is a critical event in signal transduction. All (p)2ITAMs, but nottheir nonphosphorylated counterparts, induced extensive protein tyrosinephosphorylation in permeabilised cells. After binding of the ligand via an SH2domain, phosphorylation of the two conserved tyrosines of ITAM creates binding sites for downstream signalling molecules and thus enables the initiation of signalling events. This phosphorylation was found to reflect activation of the src family kinases Lyn and Syk. Different ITAMs may preferentially activate distinct signalling pathways as a consequence of distinct SH2 effector binding preference [, ]. Furthermore, in viruses, ITAMs may play key roles in viral pathogenesis by regulating viral clearance, immune cell activation, immune cell recruitment through binding of cellular kinases and thereby down regulate their function [].This motif can be found in one to three copies and in association with the Ig-like domain. Proteins currently known to contain an ITAM motif are:Mammalian alpha and beta immunoglobulin proteins, TCR gamma receptors, FCR gamma receptors subunits, CD3 chains receptors and NFAT activation molecule.Hantavirus cytoplasmic elements.
The SH2-containing Shc adapter proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to the Ras/mitogen-activated protein kinase (MAPK) pathway []. Three Shc genes were originally identified in mammals that encode proteins characterised by an amino-terminal phosphotyrosine binding (PTB) domain and a carboxy-terminal Src homology 2 domain. Shc1 (ShcA) is ubiquitously expressed, whereas expression of Shc2 (ShcB) and Shc3 (ShcC) appears to be limited to neuronal cells [].SHC is composed of an N-terminal domain that interacts with proteins containing phosphorylated tyrosines, a (glycine/proline)-rich collagen-homology domain that contains the phosphorylated binding site, and a C-terminal SH2 domain. SH2 has been shown to interact with the tyrosine-phosphorylated receptors of EGF and PDGF and with the tyrosine-phosphorylated C chain of the T-cell receptor, providing one of the mechanisms of T-cell-mediated Ras activation []. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [, , ].
ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells []. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function []. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands []. This entry contains the N terminus SH2 domains of both Syk and Zap70.
The PX (phox) domain []occurs in a variety of eukaryotic proteins and have been implicated in highly diverse functions such as cell signalling, vesicular trafficking, protein sorting and lipid modification [, , , ]. PX domains are important phosphoinositide-binding modules that have varying lipid-binding specificities []. The PX domain is approximately 120 residues long [], and folds into a three-stranded β-sheet followed by three -helices and a proline-rich region that immediately preceeds a membrane-interaction loop and spans approximately eight hydrophobic and polar residues. The PX domain of neutrophil cytosol factor 1 (p47phox) binds to the SH3 domain in the same protein []. Phosphorylation of p47(phox), a cytoplasmic activator of the microbicidal phagocyte oxidase (phox), elicits interaction of p47(phox) with phoinositides. The protein phosphorylation-driven conformational change of p47(phox) enables its PX domain to bind to phosphoinositides, the interaction of which plays a crucial role in recruitment of p47(phox) from the cytoplasm to membranes and subsequent activation of the phagocyte oxidase. The lipid-binding activity of this protein is normally suppressed by intramolecular interaction of the PX domain with the C-terminal Src homology 3 (SH3) domain [].The PX domain is conserved from yeast to human. A multiple alignment of representative PX domain sequences from eukaryotic proteins [], shows relatively little sequence conservation, although their structure appears to be highly conserved. Although phosphatidylinositol-3-phosphate (PtdIns(3)P) is the primary target of PX domains, binding to phosphatidic acid, phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), and phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) has been reported as well. The PX-domain is also a protein-protein interaction domain [].
Ephrins and their receptors EphR play an important role in cell communication in normal physiology, as well as in disease pathogenesis [, ]. Binding of the ephrin (Eph) ligand to EphR requires cell-cell contact, since both molecules are anchored to the plasma membrane. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling, depending on Eph kinase activity) and ephrin-expressing cells (reverse signaling) [, , ]. Eph signaling controls cell morphology, adhesion, migration and invasion.Ephrins can be subdivided into two groups, A and B, depending on their respective receptors EphA or EphB. The nine human EphA receptors bind to five GPI-linked ephrin-A ligands []. Interactions are promiscuous within each class, and some Eph receptors can also bind to ephrins of the other class. All ephrin As contain a highly conserved receptor binding ectodomain described by this entry. Although ephrin As do not have a cytoplasmic tail (in contrast to ephrin Bs), they are still capable of downstream activation of Src family kinases and phosphoinositide-3-kinases, most likely involving co-receptors such as neurotrophin receptors [, ].
The PX (phox) domain []occurs in a variety of eukaryotic proteins and have been implicated in highly diverse functions such as cell signalling, vesicular trafficking, protein sorting and lipid modification [, , , ]. PX domains are important phosphoinositide-binding modules that have varying lipid-binding specificities []. The PX domain is approximately 120 residues long [], and folds into a three-stranded β-sheet followed by three -helices and a proline-rich region that immediately preceeds a membrane-interaction loop and spans approximately eight hydrophobic and polar residues. The PX domain of neutrophil cytosol factor 1 (p47phox) binds to the SH3 domain in the same protein []. Phosphorylation of p47(phox), a cytoplasmic activator of the microbicidal phagocyte oxidase (phox), elicits interaction of p47(phox) with phoinositides. The protein phosphorylation-driven conformational change of p47(phox) enables its PX domain to bind to phosphoinositides, the interaction of which plays a crucial role in recruitment of p47(phox) from the cytoplasm to membranes and subsequent activation of the phagocyte oxidase. The lipid-binding activity of this protein is normally suppressed by intramolecular interaction of the PX domain with the C-terminal Src homology 3 (SH3) domain [].The PX domain is conserved from yeast to human. A multiple alignment of representative PX domain sequences from eukaryotic proteins [], shows relatively little sequence conservation, although their structure appears to be highly conserved. Although phosphatidylinositol-3-phosphate (PtdIns(3)P) is the primary target of PX domains, binding to phosphatidic acid, phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), and phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) has been reported as well. The PX-domain is also a protein-protein interaction domain [].
This entry represents the RNA recognition motif (RRM) of synaptojanin-1. Synaptojanin-1 was originally identified as one of the major Grb2-binding proteins that may participate in synaptic vesicle endocytosis []. It also acts as an Src homology 3 (SH3) domain-binding brain-specific inositol 5-phosphatase, with a putative role in clathrin-mediated endocytosis [, ]. Synaptojanin-1 contains an N-terminal domain homologous to the cytoplasmic portion of the yeast protein Sac1p [], a central inositol 5-phosphatase domain followed by a putative RNA recognition motif (RRM), and a C-terminal proline-rich region mediating the binding of synaptojanin-1 to various SH3 domain-containing proteins including amphiphysin, SH3p4, SH3p8, SH3p13, and Grb2 []. Synaptojanin-1 has two tissue-specific alternative splicing isoforms, synaptojanin-145 expressed in brain and synaptojanin-170 expressed in peripheral tissues. Synaptojanin-145 is very abundant in nerve terminals and may play an essential role in the clathrin-mediated endocytosis of synaptic vesicles []. In contrast to synaptojanin-145, synaptojanin-170 contains three unique asparagine-proline-phenylalanine (NPF) motifs in the C-terminal region, and may function as a potential bindingpartner for Eps15, a clathrin coat-associated protein acting as a major substrate for the tyrosine kinase activity of the epidermal growth factor receptor [].
Synaptojanin-1 was originally identified as one of the major Grb2-binding proteins that may participate in synaptic vesicle endocytosis []. It also acts as an Src homology 3 (SH3) domain-binding brain-specific inositol 5-phosphatase, with a putative role in clathrin-mediated endocytosis [, ]. Synaptojanin-1 contains an N-terminal domain homologous to the cytoplasmic portion of the yeast protein Sac1p [], a central inositol 5-phosphatase domain followed by a putative RNA recognition motif (RRM), and a C-terminal proline-rich region mediating the binding of synaptojanin-1 to various SH3 domain-containing proteins including amphiphysin, SH3p4, SH3p8, SH3p13, and Grb2 []. Synaptojanin-1 has two tissue-specific alternative splicing isoforms, synaptojanin-145 expressed in brain and synaptojanin-170 expressed in peripheral tissues. Synaptojanin-145 is very abundant in nerve terminals and may play an essential role in the clathrin-mediated endocytosis of synaptic vesicles []. In contrast to synaptojanin-145, synaptojanin-170 contains three unique asparagine-proline-phenylalanine (NPF) motifs in the C-terminal region, and may function as a potential binding partner for Eps15, a clathrin coat-associated protein acting as a majorsubstrate for the tyrosine kinase activity of the epidermal growth factor receptor [].
The PX domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions such as cell signaling, vesicular trafficking, protein sorting, and lipid modification, among others. p47phox is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species []. p47phox is required for activation of NADH oxidase and plays a role in translocation [].Neutrophil cytosol factor 1 (also known as p47phox) contains anN-terminal PX domain, two Src Homology 3 (SH3) domains, and a C-terminal domain that contains PxxP motifs for binding SH3 domains. The PX domain of p47phox is unique in that it contains two distinct basic pockets on the membrane-binding surface: one preferentially binds phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2]and is analogous to the PI3P-binding pocket of p40phox, while the other binds anionic phospholipids such as phosphatidic acid or phosphatidylserine. Simultaneous binding in the two pockets results in increased membrane affinity [, ]. The PX domain of p47phox is also involved in protein-protein interaction.
Jak2 is widely expressed in many tissues. It is essential for the signaling of hormone-like cytokines such as growth hormone, erythropoietin, thrombopoietin, and prolactin, as well as some IFNs and cytokines that signal through the IL-3 and gp130 receptors []. Disruption of Jak2 in mice results in an embryonic lethal phenotype with multiple defects including erythropoietic and cardiac abnormalities []. It is the only Jak gene that results in a lethal phenotype when disrupted in mice. A mutation in the pseudokinase domain of Jak2, V617F, is present in many myeloproliferative diseases, including almost all patients with polycythemia vera, and 50% of patients with essential thrombocytosis and myelofibrosis [, , , ].Jak2 is a cytoplasmic (or nonreceptor) PTK containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal tyr kinase domain. The pseudokinase domain shows similarity to tyr kinases but lacks crucial residues for catalytic activity and ATP binding. Despite this, the presumed pseudokinase (repeat 1) domain of Jak2 exhibits dual-specificity kinase activity, phosphorylating two negative regulatory sites in Jak2: Ser523 and Tyr570. Inactivation of the repeat 1 domain increased Jak2 basal activity, suggesting that it modulates the kinase activity of the C-terminal catalytic (repeat 2) domain [].This entry represents the pseudokinase domain of Jak2.
Jak2 is widely expressed in many tissues. It is essential for the signaling of hormone-like cytokines such as growth hormone, erythropoietin, thrombopoietin, and prolactin, as well as some IFNs and cytokines that signal through the IL-3 and gp130 receptors []. Disruption of Jak2 in mice results in an embryonic lethal phenotype with multiple defects including erythropoietic and cardiac abnormalities []. It is the only Jak gene that results in a lethal phenotype when disrupted in mice. A mutation in the pseudokinase domain of Jak2, V617F, is present in many myeloproliferative diseases, including almost all patients with polycythemia vera, and 50% of patients with essential thrombocytosis and myelofibrosis [, , , ].Jak2 is a cytoplasmic (or nonreceptor) PTK containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal tyr kinase domain. The pseudokinase domain shows similarity to tyr kinases but lacks crucial residues for catalytic activity and ATP binding. Despite this, the presumed pseudokinase (repeat 1) domain of Jak2 exhibits dual-specificity kinase activity, phosphorylating two negative regulatory sites in Jak2: Ser523 and Tyr570. Inactivation of the repeat 1 domain increased Jak2 basal activity, suggesting that it modulates the kinase activity of the C-terminal catalytic (repeat 2) domain [].This entry represents the C-terminal catalytic domain.
The caspase recruitment domain (CARD domain) is a homotypic protein interaction module composed of a bundle of six α-helices. CARD is related in sequence and structure to the death domain (DD, see ) and the death effector domain (DED, see ), which work in similar pathways and show similar interaction properties []. The CARD domain typically associates with other CARD-containing proteins, forming either dimers or trimers. CARD domains can be found in isolation, or in combination with other domains. Domains associated with CARD include: NACHT () (in Nal1 and Bir1), NB-ARC () (in Apaf-1), pyrin/dapin domains () (in Nal1), leucine-rich repeats () (in Nal1), WD repeats () (in Apaf1), Src homology domains (), PDZ (), RING, kinase and DD domains [].CARD-containing proteins are involved in apoptosis through their regulation of caspases that contain CARDs in their N-terminal pro-domains, including human caspases 1, 2, 9, 11 and 12 [, ]. CARD-containing proteins are also involved in inflammation through their regulation of NF-kappaB []. The mechanisms by which CARDs activate caspases and NF-kappaB involve the assembly of multi-protein complexes, which can facilitate dimerisation or serve as scaffolds on which proteases and kinases are assembled and activated.
The SH2-containing Shc adapter proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to the Ras/mitogen-activated protein kinase (MAPK) pathway []. Three Shc genes were originally identified in mammals that encode proteins characterised by an amino-terminal phosphotyrosine binding (PTB) domain and a carboxy-terminal Src homology 2 domain. Shc1 (ShcA) is ubiquitously expressed, whereas expression of Shc2 (ShcB) and Shc3 (ShcC) appears to be limited to neuronal cells [].A fourth Shc family protein, ShcD/Shc4, is expressed in adult brain and skeletal muscle. ShcD can associate via its PTB domain with the phosphorylated muscle-specific kinase (MuSK) receptor tyrosine kinase and undergo tyrosine phosphorylation downstream of activated MuSK. Therefore, ShcD may mediate a specific aspect of signalling downstream of the MuSK receptor []. ShcD also interacts with EGFR receptor (epidermal growth factor receptor) and facilitates its ligand-independent phosphorylation []. ShcD has been shown to be a modulator in the transition of embryonic stem cell (ESC) to epiblast stem cells (EpiSCs), the initial step for ESCs to commit to differentiation [].
Protein-tyrosine kinase 2-beta (PTK2B), also known as focal adhesion kinase 2 (FAK2), proline-rich tyrosine kinase 2 (PYK2), related adhesion focal tyrosine kinase (RAFTK), or calcium-dependent tyrosine kinase (CADTK), is a non-receptor protein-tyrosine kinase that is structurally similar to FAK []. FAK and PYK2 may be involved in several overlapping signalling pathways [, ]. FAK is expressed ubiquitously, whereas PYK2 expression is restricted to the endothelium, central nervous system, and hematopoietic lineages. PYK2 contains a central tyrosine kinase domain flanked by an N-terminal FERM domain, which mediates the binding of PYK2 to multiple proteins, and a C-terminal focal adhesion targeting (FAT) domain []. PYK2 is sensitive to intracellular Ca+ signalling and G-protein-coupled receptors [, ].PYK2 plays a critical role in the migration of multiple cell lineages induced by growth factor, cytokine and integrin receptors. PYK2 alters the migratory ability of these cells by directly phosphorylating proteins that link focal adhesions to the actin cytoskeleton. It also recruits Src family kinases and other signalling proteins to focal adhesions, and directly alters actin cytoskeleton rearrangement via regulating the activity of Rac [, , ]. It has roles in T-cells [], macrophages [], bone formation [, , ],and vascular function [].
Amphiphysins belong to the expanding BAR (Bin-Amphiphysin-Rvsp) family proteins, all members of which share a highly conserved N-terminal BAR domain, which has predicted coiled-coil structures required for amphiphysin dimerisation and plasma membrane interaction []. Almost all members also share a conserved C-terminal Src homology 3 (SH3) domain, which mediates their interactions with the GTPase dynamin and the inositol-5'-phosphatase synaptojanin 1 in vertebrates and with actin in yeast. The central region of all these proteins is most variable. In mammals, the central region of amphiphysin I and amphiphysin IIa contains a proline-arginine-rich region for endophilin binding and a CLAP domain, for binding to clathrin and AP-2. The interactions mediated by both the central and C-terminal domains arebelieved to be modulated by protein phosphorylation [, ].Amphiphysins are proteins that are thought to be involved in clathrin-mediated endocytosis, actin function, and signalling pathways. In vertebrates, amphiphysins may regulate, but are not essential for clathrin-mediated endocytosis of SVs. However, in Drosophila amphiphysin is not involved at all in SV endocytosis but is required for T-tubule structure and excitation-contraction coupling muscles and plays a role in membrane morphogenesis in developing photoreceptors and a variety of other cells [].Amphiphysin 2 was the second amphiphysin family member found in mammals.The gene encoding it has been found to be alternatively spliced. Thevarious products have been named: BIN-1, Sh3P9, BRAMP-2 and ALP-1. Theyhave different distribution patterns, with the largest form (~95 kD) beingexpressed solely in the brain, where it shares a very similar (if notidentical) distribution pattern to amphiphysin 1 [].
The SH2-containing Shc adapter proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to the Ras/mitogen-activated protein kinase (MAPK) pathway []. Three Shc genes were originally identified in mammals that encode proteins characterised by an amino-terminal phosphotyrosine binding (PTB) domain and a carboxy-terminal Src homology 2 domain. Shc1 (ShcA) is ubiquitously expressed, whereas expression of Shc2 (ShcB) and Shc3 (ShcC) appears to be limited to neuronal cells [].Shc1 (ShcA) adaptor transduces phosphotyrosine-dependent signals downstream of receptor tyrosine kinases (RTK) and non-RTKs, which regulates signalling pathways in breast cancer cells []. Its SH2 domain is critical for tumour survival during mammary tumorigenesis [], while its PTB domain functions as a biological sensor of phosphotyrosine signalling during breast cancer progression []. Shc1 is required for transforming growth factor beta (TGF-beta)-induced breast cancer cell migration, invasion, and metastasis []. It is also involved in signalling downstream of the angiopoietin receptor TEK/TIE2, and plays a role in the regulation of endothelial cell migration and sprouting angiogenesis [].
Hakai is an E3 ubiquitin ligase that disrupts cell-cell contacts in epithelial cells and is upregulated in human colon and gastric adenocarcinomas. It was identified to mediate the posttranslational downregulation of E-cadherin (CDH1), a major component of adherens junctions in epithelial cells and a potent tumour suppressor [, , ]. It also promotes ubiquitination of several other tyrosine-phosphorylated Src substrates, including cortactin (CTTN) and DOK1 []. Hakai acts as a homodimer with a novel HYB (Hakai pTyr-binding) domain that forms a phosphotyrosine-binding pocket upon, and consists of a pair of monomers arranged in an anti-parallel configuration. Each monomer contains a C3HC4-type RING-HC finger and a short pTyr-B domain that incorporates a novel, atypical C2H2-type Zn-finger coordination motif. Both domains are important for dimerization [, ]. ZNF645, also known as CBLL2, is a novel testis-specific E3 ubiquitin-protein ligase that plays a role in sperm production and quality control []. It has a structure similar to that of the c-Cbl-like protein Hakai. In contrast to Hakai, its HYB domain demonstrates different target specificities. It interacts with v-Src-phosphorylated E-cadherin, but not to cortactin [].
Hakai is an E3 ubiquitin ligase that disrupts cell-cell contacts in epithelial cells and is upregulated in human colon and gastric adenocarcinomas. It was identified to mediate the posttranslational downregulation of E-cadherin (CDH1), a major component of adherens junctions in epithelial cells and a potent tumour suppressor [, , ]. It also promotes ubiquitination of several other tyrosine-phosphorylated Src substrates, including cortactin (CTTN) and DOK1 []. Hakai acts as a homodimer with a novel HYB (Hakai pTyr-binding) domain that forms a phosphotyrosine-binding pocket upon, and consists of a pair of monomers arranged in an anti-parallel configuration. Each monomer contains a C3HC4-type RING-HC finger and a short pTyr-B domain that incorporates a novel, atypical C2H2-type Zn-finger coordination motif. Both domains are important for dimerization [, ]. ZNF645, also known as CBLL2, is a novel testis-specific E3 ubiquitin-protein ligase that plays a role in sperm production and quality control []. It has a structure similar to that of the c-Cbl-like protein Hakai. In contrast to Hakai, its HYB domain demonstrates different target specificities. It interacts with v-Src-phosphorylated E-cadherin, but not to cortactin [].
This entry represent the first SH3 domain of Nck1. The first SH3 domain of Nck binds the PxxDY sequence in the CD3e cytoplasmic tail; this binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression [].Nck1 (also called Nck-alpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling []. It binds and activates RasGAP, resulting in the downregulation of Ras []. It is also involved in the signaling of endothilin-mediated inhibition of cell migration [].Cytoplasmic proteins Nck are non-enzymatic adaptor proteins composed of three SH3 (Src homology 3) domains and a C-terminal SH2 domain []. They regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates []. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics []. They associate with tyrosine-phosphorylated growth factor receptors or their cellular substrates [, ]. There are two vertebrate Nck proteins, Nck1 and Nck2.
