This domain has been annotated as Rac1-binding domain [, ]. It can be found in human CYRIA/CYRIB and at the N terminus of CYFIP1/2 []. CYFIP proteins are known RAC1 effectors that stimulate actin polymerization []. CYRIA/B are also localised to early macropinosomes and act to modulate their formation by regulating Rac1 signalling []. In mice, CYRIB (also known as CYRI or FAM49B) negatively regulates RAC1-driven cytoskeletal remodelling and plays a role in restricting infection mediated by Mycobacterium tuberculosis and Listeria monocytogenes [].
This entry includes CYRI (CYFIP-related Rac interactor) from Dictyostelium and its homologues, CYRIA/CYRIB, from animals. CYRI binds activated Rac1 via a domain of unknown function (DUF1394). It plays important roles in cell migration, chemotaxis and pathogen entry into cells. It controls actin dynamics through Rac1, the Scar/WAVE Complex and the Arp2/3 Complex [, ]. In mice, CYRIB (also known as CYRI or FAM49B) negatively regulates RAC1-driven cytoskeletal remodelling and plays a role in restricting infection mediated by Mycobacterium tuberculosis and Listeria monocytogenes [].
Synaptojanin-2 is a ubiquitously expressed central regulatory enzyme in the phosphoinositide-signaling cascade []. As a novel Rac1 effector regulating an early step of clathrin-mediated endocytosis, synaptojanin-2 acts as a polyphosphoinositide phosphatase, directly and specifically interacting with Rac1 in a GTP-dependent manner. It mediates the inhibitory effect of Rac1 on endocytosis and plays an important role in the Rac1-mediated control of cell growth []. Synaptojanin-2 shows high sequence homology to the N-terminal Sac1p homology domain [], the central inositol 5-phosphatase domain, and the putative RNA recognition motif (RRM) of synaptojanin-1, but differs in the proline-rich region.
This entry represents the RNA recognition motif (RRM) of synaptojanin-2. Synaptojanin-2 is a ubiquitously expressed central regulatory enzyme in the phosphoinositide-signaling cascade []. As a novel Rac1 effector regulating an early step of clathrin-mediated endocytosis, synaptojanin-2 acts as a polyphosphoinositide phosphatase, directly and specifically interacting with Rac1 in a GTP-dependent manner. It mediates the inhibitory effect of Rac1 on endocytosis and plays an important role in the Rac1-mediated control of cell growth []. Synaptojanin-2 shows high sequence homology to the N-terminal Sac1p homology domain [], the central inositol 5-phosphatase domain, and the putative RNA recognition motif (RRM) of synaptojanin-1, but differs in the proline-rich region.
The Rac1-binding domain is the C-terminal portion of YpkA from Yersinia. It is an all-helical molecule consisting of two distinct subdomains connected by a linker. The N-terminal end of this domain (residues 434-615) consists of six helices organised into two three-helix bundles packed against each other. This region is involved with binding to GTPases. The C-terminal end (residues 705-732) is a novel and elongated fold consisting of four helices clustered into two pairs, and this fold carries the helix implicated in actin activation. The Rac1-binding domain mimics host guanidine nucleotide dissociation inhibitors (GDIs) of the Rho GTPases, thereby inhibiting nucleotide exchange in Rac1 and causing cytoskeletal disruption in the host [].This superfamily represents the C-terminal subdomain of the Rac1-binding domain. This domain is made up of one long, kinked helix and three smaller helices. The long helix has 2 points of contact which allow the domain to bind Rac1 at regions called Switch I and Switch II on the Rac1 protein.
MTSS2 (also known as MTSS1-like protein, MTSS1L, or ABBA) is an I-BAR (Bin/amphipysin/Rvs) domain containing protein. BAR domain forms an anti-parallel all-helical dimer, with a curved (banana-like) shape, that promotes membrane tubulation. BAR domain proteins can be classified into three types: BAR, F-BAR and I-BAR. BAR and F-BAR proteins generate positive membrane curvature, while I-BAR proteins induce negative curvature []. MTSS2 contains an additional C-terminal WH2 domain that binds G-actin [].MTSS2 is a regulator of actin and plasma membrane dynamics in radial glial cells []. It binds the small GTPase Rac1 through its I-BAR domain and promotes PDGF-mediated membrane ruffling by activating Rac1 [].
Protein RCC2 (also known as TD-60) interacts with microtubules and is required for completion of mitosis and cytokinesis []. It may function as a guanine nucleotide exchange factor for the small GTPase RAC1 [].This entry also includes some uncharacterised bacterial proteins.
This entry represent the RhoGAP domain found in ARHGAP6 and ARHGAP36.Rho GTPase activating protein 6 (ARHGAP6/RHOGAP6) shows GAP activity towards RhoA, but not towards Cdc42 and Rac1 []. ARHGAP6 is often deleted in microphthalmia with linear skin defects syndrome (MLS); MLS is a severe X-linked developmental disorder []. ARHGAP36 is a potent antagonist of PKAsignalling [].
PREX2 functions as a RAC1 guanine nucleotide exchange factor (GEF), activating Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein []. It contains an N-terminal RhoGEF domain, two DEP and PDZ domains.This entry represents the first DEP domain of PREX2.
Rho GTPase activating protein 6 (ArhGAP6/RHOGAP6) shows GAP activity towards RhoA, but not towards Cdc42 and Rac1 []. ArhGAP6 is often deleted in microphthalmia with linear skin defects syndrome (MLS); MLS is a severe X-linked developmental disorder [].This family also includes ARHGAP36, which is a potent antagonist of PKA signalling [].
RhoG is a GTPase with high sequence similarity to members of the Rac subfamily, including the regions involved in effector recognition and binding. However, RhoG does not bind to known Rac1 and Cdc42 effectors, including proteins containing a Cdc42/Rac interacting binding (CRIB) motif. Instead, RhoG interacts directly with Elmo, an upstream regulator of Rac1, in a GTP-dependent manner and forms a ternary complex with Dock180 to induce activation of Rac1 []. The RhoG-Elmo-Dock180 pathway is required for activation of Rac1 and cell spreading mediated by integrin, as well as for neurite outgrowth induced by nerve growth factor. Thus RhoG activates Rac1 through Elmo and Dock180 to control cell morphology []. RhoG has also been shown to play a role in caveolar trafficking []and has a novel role in signaling the neutrophil respiratory burst stimulated by G protein-coupled receptor (GPCR) agonists []. Most Rho proteins contain a lipid modification site at the C terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins.
T-lymphoma invasion and metastasis-inducing protein 1 (Tiam1) is a guanine exchange factor (GEF) for CDC42 and the Rho-family GTPase Rac1, which plays an important role in cell-matrix adhesion and in cell migration [, ]. Tiam1 is involved in multiple steps of tumorigenesis [].Tiam2 has been shown to localise to the nuclear envelope and to regulate Rac1 activity at the nuclear envelope which regulates the perinuclear actin cap []. It has been shown to promote invasion and motility of non-small cell lung cancer cells []. It has also been shown to promote epithelial-to-mesenchymal transition and results in proliferation and invasion in liver cancer cells []. This entry includes a group of guanine nucleotide exchange factors, including Tiam1/2 from humans and Sif from Drosophila [, , ]. Tiam1/2 are activators of the Rho GTPase Rac1 and critical for cell morphology, adhesion, migration, and polarity [].
This domain represents the RNA recognition motif found in Synaptojanin proteins.Synaptojanins are phosphoinositide phosphatases known to play an important role in vesicle recycling by promoting the uncoating of clathrin following synaptic vesicle uptake [, , , , ]. 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-2 is a ubiquitously expressed central regulatory enzyme in the phosphoinositide-signaling cascade []. As a novel Rac1 effector regulating an early step of clathrin-mediated endocytosis, synaptojanin-2 acts as a polyphosphoinositide phosphatase, directly and specifically interacting with Rac1 in a GTP-dependent manner. Synaptojanin-2 shows high sequence homology to the N-terminal Sac1p homology domain [], the central inositol 5-phosphatase domain, and the putative RNA recognition motif (RRM) of synaptojanin-1, but differs in the proline-rich region.
This entry represents leucine-rich repeat-containing protein 16A (LRRC16A). In humans it is also known as CARMIL1, which belongs to the CARMIL (capping protein, Arp2/3 and Myosin-I linker) family. CARMIL family members are potential regulators of actin capping proteins, which control the polymerisation of actin filaments by capping their barbed ends [, ]. CARMIL1 is essential for cell migration and may control lamellipodial actin assembly via effects on Trio and Rac1 [, ].
This entry represents the third SH3 domain, located in the middle, of SH3RF3.SH3RF3 (also known as POSH2) is a scaffold protein with E3 ubiquitin-protein ligase activity []. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions []. It also interacts with GTP-loaded Rac1 []. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains.
Nck-associated protein 1 is part of lamellipodial complex that controls Rac-dependent actin remodeling [, ]. It associates preferentially with the first SH3 domain of Nck and is a component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 and WASF2/WAVE2. It is also a component of the WAVE1 complex composed of ABI2, CYFIP2, C3orf10/HSPC300, NCKAP1 and WASF1/WAVE1. CYFIP2 binds to activated RAC1 which causes the complex to dissociate, releasing activated WASF1. The complex can also be activated by NCK1. Expression of this protein was found to be markedly reduced in patients with Alzheimer's disease [].
The Rac1-binding domain is the C-terminal portion of YpkA from Yersinia. It is an all-helical molecule consisting of two distinct subdomains connected by a linker. The N-terminal end of this domain (residues 434-615) consists of six helices organised into two three-helix bundles packed against each other. This region is involved with binding to GTPases. The C-terminal end (residues 705-732) is a novel and elongated fold consisting of four helices clustered into two pairs, and this fold carries the helix implicated in actin activation. The Rac1-binding domain mimics host guanidine nucleotide dissociation inhibitors (GDIs) of the Rho GTPases, thereby inhibiting nucleotide exchange in Rac1 and causing cytoskeletal disruption in the host [].
SR-25, otherwise known as ADP-ribosylation factor-like factor 6-interacting protein 4, is expressed in virtually all tissue types. At the N terminus there is a repeat of serine-arginine (SR repeat), and towards the middle of the protein there are clusters of both serines and of basic amino acids. The presence of many nuclear localisation signals strongly implies that this is a nuclear protein that may contribute to RNA splicing []. SR-25 is also implicated, along with heat-shock-protein-27, as a mediator in the Rac1 (GTPase ras-related C3 botulinum toxin substrate 1; also see ) signalling pathway [].
This entry represents the SH3 domain of DBS.DBS, also called MCF2L or OST, functions as a Rho GTPase guanine nucleotide exchange factor (RhoGEF), facilitating the exchange of GDP and GTP. It was originally isolated from a cDNA screen for sequences that cause malignant growth. It plays roles in regulating clathrin-mediated endocytosis and cell migration through its activation of Rac1 and Cdc42 [, ]. Depending on cell type, DBS can also activate RhoA and RhoG [, ]. DBS contains a Sec14-like domain [], spectrin-like repeats, a RhoGEF or Dbl homology (DH) domain, a Pleckstrin homology (PH) domain [], and an SH3 domain.
SH3RF1 (or POSH) and SH3RF3 (or POSH2) are scaffold proteins that function as E3 ubiquitin-protein ligases. They contain an N-terminal RING finger domain and four SH3 domains []. This entry represents the fourth SH3 domain, located at the C terminus of SH3RF1 and SH3RF3, and similar domains. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp []. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis []. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1 [].
There are two forms of Pix proteins: alpha Pix (also called Rho guanine nucleotide exchange factor (GEF) 6, 90Cool-2 or ARHGEF6) and beta Pix (GEF7, p85Cool-1 or ARHGEF7), which activate small GTPases by exchanging bound GDP for free GTP. betaPix contains an N-terminal SH3 domain, a RhoGEF/DH domain, a PH domain, a GIT1 binding domain (GBD), and a C-terminal coiled-coil (CC) domain []. It acts as a GEF for both Cdc42 and Rac1 [], and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion [, , , ]. alphaPix differs in that it contains a calponin homology (CH) domain, which interacts with beta-parvin, N-terminal to the SH3 domain. alphaPix is an exchange factor for Rac1 and Cdc42 and mediates Pak activation on cell adhesion to fibronectin. Mutations in alphaPix can cause X-linked mental retardation. alphaPix also interacts with Huntington's disease protein (htt), and enhances the aggregation of mutant htt (muthtt) by facilitating SDS-soluble muthtt-muthtt interactions. The DH-PH domain of a Pix was required for its binding to htt. In the majority of Rho GEF proteins, the DH-PH domain is responsible for the exchange activity [, , , , ].This entry represents the PH domain of ARHGEF6 and ARHGEF7.
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases []. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [, ]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. This entry represents DOCK2 (dedicator of cytokinesis 2). DOCK2 is involved in cytoskeletal rearrangements required for lymphocyte migration in response of chemokines. It activates RAC1 and RAC2, but not CDC42, by functioning as a guanine nucleotide exchange factor (GEF), which exchanges bound GDP for free GTP. It may also participate in IL2 transcriptional activation via the activation of RAC2 [].
Epithelial Cell Transforming Sequence 2 (Ect2) is a guanine nucleotide exchange factor (GEF) that catalyses the exchange of GDP for GTP. Like other GEFs, Ect2 serves as molecular switches in diverse signaling pathways, including cell polarity, mitotic spindle assembly, cytokinesis, etc [, , ]. Ect2 interacts with several members of the Rho GTPase family including, RhoA, RhoB, RhoC, RhoG, Rac1 and Cdc42 [, , , , ]. Ect2 regulates the formation of the actomyosin contractile ring at mitotic exit through activation of RhoA and functions in metaphase for the process of spindle assembly through activation of Cdc42 []. Ect2 is regulated through a number of mechanisms including phosphorylation, intracellular localization and intra- and inter-molecular interactions []. Ect2 is established as a human oncogene []. It is highly expressed in a variety of human tumors including brain lung, bladder, esophageal, pancreatic and ovarian tumors [, , , , ]. Ect2 is also suggested to play a role in neuronal differentiation and brain development [].
The adaptor protein 3BP2/SH3BP2 is a cytoplasmic adaptor that contributes to the regulation of immune responses []. The protein-tyrosine kinase Syk phosphorylates 3BP2 which results in the activation of Rac1 through the interaction with the SH2 domain of Vav1 and induces the binding to the SH2 domain of the upstream protein-tyrosine kinase Lyn and enhances its kinase activity []. 3BP2 has a positive regulatory role in IgE-mediated mast cell activation []. In lymphocytes, engagement of T cell or B cell receptors triggers tyrosine phosphorylation of 3BP2 []. 3BP2 is required for the proliferation of B cells and B cell receptor signaling. Mutations in the 3BP2 gene are responsible for cherubism resulting in excessive bone resorption in the jaw [].This entry represents the SH2 domain of SH3BP2.
Members of Rho family are small G proteins that transduce signals from plasma-membrane receptors and control cell adhesion, motility and shape by actin cytoskeleton formation. Like all other GTPases, Rho proteins act as molecular switches, with an active GTP-bound form and an inactive GDP-bound form. The active conformation is promoted by guanine-nucleotide exchange factors, and the inactive state by GTPase-activating proteins (GAPs), which stimulate the intrinsic GTPase activity of small G proteins.This entry represents Rho GTPase activating protein 27 (ARHGAP27, also known as CIN85-associated multi-domain-containing Rho GTPase-activating protein 1, CAMGAP1), a binding protein for Cbl-interacting protein of 85kDa (CIN85), an adaptor protein involved in the endocytic process of several receptor tyrosine kinases. It also has activity towards Rac1 and Cdc42 [].
VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42 []. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others [, , , , ]. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins [, , ].This entry represents the second SH3 domain of VAV2.
VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42 []. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others [, , , , ]. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins [, , ].This entry represents the first SH3 domain of VAV2.
VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1 []. It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration []. It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity [, ]. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. This entry represents the SH3 domain of VAV3. The SH3 domain of VAV3 is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins [].
Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac1 [], and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion [, , , ].PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs [, ].This entry represents the SH3 domain of beta-PIX.
This entry represents the PH domain of guanine nucleotide exchange factor DBS. The DBS PH domain participates in binding to both the Cdc42 and RhoA GTPases []. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner [].DBS, also called MCF2L or OST, functions as a Rho GTPase guanine nucleotide exchange factor (RhoGEF), facilitating the exchange of GDP and GTP. It was originally isolated from a cDNA screen for sequences that cause malignant growth. It plays roles in regulating clathrin-mediated endocytosis and cell migration through its activation of Rac1 and Cdc42 [, ]. Depending on cell type, DBS can also activate RhoA and RhoG [, ]. DBS contains a Sec14-like domain [], spectrin-like repeats, a RhoGEF or Dbl homology (DH) domain, a Pleckstrin homology (PH) domain [], and an SH3 domain.
This entry includes cytoplasmic fragile X messenger ribonucleoprotein 1-interacting proteins from humans and their homologues, such as Sra-1 (specifically Rac1-associated protein 1) from Drosophila and PIROGI from Arabidopsis. In humans, there are two members, CYFIP1 and CYFIP2. They both interact with FMRP (Fragile X messenger ribonucleoprotein 1), which is responsible for pathologic manifestations in the Fragile X Syndrome. CYFIP1 interacts with the small GTPase Rac1 [, ]. CYFIP1 represses cap-dependent translation of mRNA by interacting with the initiation factor eIF4E []. CYFIP1 and CYFIP2 are part of the Wiskott-Aldrich syndrome protein-family verprolin-homologous protein (WAVE) complex that regulates actin polymerization at synapses []. Drosophila Sra-1 interacts with the Kette and Wasp. It is required for neuronal and bristle development in Drosophila []. PIROGI is part of a WAVE complex that activates the ARP2/3 complex and is Involved in regulation of actin organization [].
The adaptor protein 3BP2/SH3BP2 is a cytoplasmic adaptor that contributes to the regulation of immune responses []. The protein-tyrosine kinase Syk phosphorylates 3BP2 which results in the activation of Rac1 through the interaction with the SH2 domain of Vav1 and induces the binding to the SH2 domain of the upstream protein-tyrosine kinase Lyn and enhances its kinase activity []. 3BP2 has a positive regulatory role in IgE-mediated mast cell activation []. In lymphocytes, engagement of T cell or B cell receptors triggers tyrosine phosphorylation of 3BP2 []. 3BP2 is required for the proliferation of B cells and B cell receptor signaling. Mutations in the 3BP2 gene are responsible for cherubism resulting in excessive bone resorption in the jaw [].
The Rac1-binding domain is the C-terminal portion of YpkA from Yersinia. It is an all-helical molecule consisting of two distinct subdomains connected by a linker. The N-terminal end of this domain (residues 434-615) consists of six helices organised into two three-helix bundles packed against each other. This region is involved with binding to GTPases. The C-terminal end (residues 705-732) is a novel and elongated fold consisting of four helices clustered into two pairs, and this fold carries the helix implicated in actin activation. The Rac1-binding domain mimics host guanidine nucleotide dissociation inhibitors (GDIs) of the Rho GTPases, thereby inhibiting nucleotide exchange in Rac1 and causing cytoskeletal disruption in the host [].This superfamily represents the N-terminal GTPase binding subdomain of the Rac1-binding domain.
This entry includes transmembrane glycoprotein EpCAM (epithelial cell adhesion molecule, also known as Trop-1) and Trop-2 (also known as tumor-associated calcium signal transducer 2, TACSTD2). They belong to the tumour-associated calcium signal transducer (TACSTD) family. They have been reported to directly interact with claudin-1 and claudin-7 [, , ]. EpCAM mediates homotypic cell contacts in epithelia tissues and regulates cell proliferation and cancer stemness. It has been used as a diagnostic marker for circulating tumour cells (CTCs) in the blood []. EpCAM has been shown to contribute to formation of intestinal barrier by recruiting claudins to cell-cell junctions []. Mutations in the EpCAM gene lead to congenital tufting enteropathy, severe intestinal epithelium homeostasis disorders, and Lynch syndrome []. Trop-2 is highly expressed in a variety of epithelial cancer cells. It has been identified as an oncogene leading to invasiveness and tumorigenesis []. It has been shown to regulate integrin-dependent signalling for cell-substrate adhesion and cell migration. It also modulates Rac1 GTPase activity and induces activation of PAK4 [].
This entry represents the ELMO (EnguLfment and Cell MOtility) domain, which is found in a number of eukaryotic proteins involved in the cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility, including CED-12, ELMO-1 and ELMO-2. ELMO-1 and ELMO-2 are components of signalling pathways that regulate phagocytosis and cell migration and are mammalian orthologues of the Caenorhabditis elegans gene, ced-12 that is required for the engulfment of dying cells and cell migration. ELMO-1/2 act in association with DOCK1 and CRK. ELMO-1/2 interact with the SH3-domain of DOCK1 via an SH3-binding site to enhance the guanine nucleotide exchange factor (GEF) activity of DOCK1. ELMO-1/2 could be part of a complex with DOCK1 and Rac1 that could be required to activate Rac Rho small GTPases. Regulatory GTPases in the Ras superfamily employ a cycle of alternating GTP binding and hydrolysis, controlled by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs), as essential features of their actions in cells. Within the Ras superfamily, the Arf family is composed of 30 members, including 22 Arf-like (Arl) proteins. The ELMO domain has been proposed to be a GAP domain for ARL2 and other members of the Arf family [].
This entry represents the oligomerisation domain of the breakpoint cluster region oncoprotein Bcr, and the Bcr/Abl (Abelson-leukemia-virus) fusion protein created by a reciprocal (9;22) fusion []. Brc displays serine/threonine protein kinase activity (), acting as a GTPase-activating protein for RAC1 and CDC42. Brc promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them []. The Bcr/Abl fusion protein loses some of the regulatory function of Bcr with regards to small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells [].The Bcr, Bcr/Abl oncoprotein oligomerisation domain consists of a short N-terminal helix (alpha-1), a flexible loop and a long C-terminal helix (alpha-2). Together these form an N-shaped structure, with the loop allowing the two helices to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil between the alpha-2 helices and domain swapping of two alpha-1 helices, where one alpha-1 helix swings back and packs against the alpha-2 helix from the second monomer. Two dimers then associate into a tetramer. The oligomerisation domain is essential for the oncogenicity of the Bcr-Abl protein [].
This entry represents a conserved region within a number of eukaryotic dedicator of cytokinesis proteins (DOCK), which are guanine nucleotide exchange factors (GEFs) [, , ], that activate some small GTPases by exchanging bound GDP for free GTP such as Rac. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis []. These proteins have a DOCK-homology region 1 (DHR-1, also known as DOCK-type C2 domain) at the N-terminal and a DHR-2 (also known as DOCKER domain) at the C-terminal. The DOCKER domain () is a GEF catalytic domain organised into three lobes, A, B and C, with the Rho-family binding site and catalytic centre generated entirely from lobes B and C. This entry represents Lobe B, which adopts an unusual architecture of two antiparallel beta sheets disposed in a loosely packed orthogonal arrangement. This lobe changes its position relative to lobe C and the bound GTPase, which suggests that lobe B distinguishes between the switch 1 conformations of the small GTPases Rac1 and Cdc42 [, ].
IRSp53, also known as IRS-58 or BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), is an I-BAR (Bin/amphipysin/Rvs) domain containing protein. BAR domain forms an anti-parallel all-helical dimer, with a curved (banana-like) shape, that promotes membrane tubulation. BAR domain proteins can be classified into three types: BAR, F-BAR and I-BAR. BAR and F-BAR proteins generate positive membrane curvature, while I-BAR proteins induce negative curvature [].IRSp53 is an adaptor protein that acts at the membrane-actin interface, coupling membrane deformation with F-actin polymerisation []. It is involved in the formation of filopodia and lamellipodia in cultured mesenchymal cells and contributes to assembly/maintenance of tight junctions in cultured epithelial cells []. IRSp53 contains an N-terminal I-BAR domain, followed by a partial CRIB domain and a SH3 domain. It binds to small GTPase Cdc42, Rac1 and WAVE1 []. IRSp53 binds Rac through its I-BAR domain and to WAVE through its SH3 domain, and thus contributes to membrane ruffling []. Its SH3 domain also interacts with other regulators of actin dynamics, such as WAVE2, Mena, mDia1, Dynamin1, Eps8 and N-WASP [].
This entry represents the oligomerisation domain of the breakpoint cluster region oncoprotein Bcr, and the Bcr/Abl (Abelson-leukemia-virus) fusion protein created by a reciprocal (9;22) fusion []. Brc displays serine/threonine protein kinase activity (), acting as a GTPase-activating protein for RAC1 and CDC42. Brc promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them []. The Bcr/Abl fusion protein loses some of the regulatory function of Bcr with regards to small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells [].The Bcr, Bcr/Abl oncoprotein oligomerisation domain consists of a short N-terminal helix (alpha-1), a flexible loop and a long C-terminal helix (alpha-2). Together these form an N-shaped structure, with the loop allowing the two helices to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil between the alpha-2 helices and domain swapping of two alpha-1 helices, where one alpha-1 helix swings back and packs against the alpha-2 helix from the second monomer. Two dimers then associate into a tetramer. The oligomerisation domain is essential for the oncogenicity of the Bcr-Abl protein [].
This entry represents the SH3 domain of IRSp53. The SH3 domain of IRSp53 has been shown to bind the proline-rich C terminus of EspFu (E. coli secreted protein F-like from prophage U) [].IRSp53, also known as IRS-58 or BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), is an I-BAR (Bin/amphipysin/Rvs) domain containing protein. BAR domain forms an anti-parallel all-helical dimer, with a curved (banana-like) shape, that promotes membrane tubulation. BAR domain proteins can be classified into three types: BAR, F-BAR and I-BAR. BAR and F-BAR proteins generate positive membrane curvature, while I-BAR proteins induce negative curvature [].IRSp53 is an adaptor protein that acts at the membrane-actin interface, coupling membrane deformation with F-actin polymerisation []. It is involved in the formation of filopodia and lamellipodia in cultured mesenchymal cells and contributes to assembly/maintenance of tight junctions in cultured epithelial cells []. IRSp53 contains an N-terminal I-BAR domain, followed by a partial CRIB domain and a SH3 domain. It binds to small GTPase Cdc42, Rac1 and WAVE1 []. IRSp53 binds Rac through its I-BAR domain and to WAVE through its SH3 domain, and thus contributes to membrane ruffling []. Its SH3 domain also interacts with other regulators of actin dynamics, such as WAVE2, Mena, mDia1, Dynamin1, Eps8 and N-WASP [].
The I-BAR domain (also known as IMD domain, IRSp53 and MIM homology domain) is a BAR-like domain of approximately 250 amino acids found at the N-terminal in the IRSp53 (insulin receptor tyrosine kinase substrate p53) and in the evolutionarily related IRSp53/MIM family. The BAR domain forms an anti-parallel all-helical dimer, with a curved (banana-like) shape, that promotes membrane tubulation. The BAR domain containing proteins can be classified into three types: BAR, F-BAR and I-BAR. BAR and F-BAR proteins generate positive membrane curvature, while I-BAR proteins induce negative curvature [, ]. The I-BAR domain containing proteins include: Vertebrate MIM (missing in metastasis), an actin-binding scaffold protein that may be involved in cancer metastasis.Vertebrate ABBA, a MIM-related protein.Vertebrate insulin receptor tyrosine kinase substrate p53 (IRSp53), a multifunctional adaptor protein that links Rac1 with a Wiskott-Aldrich syndrome family verprolin-homologous protein 2 (WAVE2) to induce lamellipodia or Cdc42 with Mena to induce filopodia [].Vertebrate IRTKS.Vertebrate Pinkbar.Drosophila melanogaster (Fruit fly) CG32082-PA.Caenorhabditis elegans M04F3.5 protein.The vertebrate I-BAR family is divided into two major groups: the IRSp53/IRTKS/Pinkbar subfamily and the MIM/ABBA subfamily. The putative invertebrate homologues are positioned between them. The IRSp53/IRTKS/Pinkbar subfamily members contain a SH3 domain, and the MIM/ABBA subfamily proteins contain a WH2 (WASP-homology 2) domain. The vertebrate SH3-containing subfamily is further divided into three groups according to the presence or absence of the WWB and the half-CRIB motif [, ]. The BAR domain binds phosphoinositide-rich vesicles with high affinity and does not display strong actin filament binding/bundling activity [, ].
This entry includes a group of RhoGEFs, including Kalirin and TRIO from mammals. Kalirin and TRIO are encoded by separate genes in mammals and by a single one in invertebrates. Kalirin and TRIO share the same complex multidomain structure and display several splice variants. They are implicated in secretory granule (SG) maturation and exocytosis [, ]. The longest Kalirin and TRIO proteins have a Sec14 domain, a stretch of spectrin repeats, a RhoGEF(DH)/PH cassette (also called GEF1), an SH3 domain, a second RhoGEF(DH)/PH cassette (also called GEF2), a second SH3 domain, Ig/FNIII domains, and a kinase domain. The first RhoGEF(DH)/PH cassette catalyzes exchange on Rac1 and RhoG while the second RhoGEF(DH)/PH cassette is specific for RhoA. Kalirin and TRIO are closely related to p63RhoGEF and have PH domains of similar function. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner [, ].Triple functional domain protein (TRIO) contains a protein kinase domain and two guanine nucleotide exchange factor (GEF) domains []. These functional domains suggest that it may play a role in signalling pathways controlling cell proliferation []. TRIO may form a complex with LAR transmembrane protein tyrosine phosphatase (PT-Pase), which localises to the ends of focal adhesions and plays an important part in coordinating cell-matrix and cytoskeletal rearrangements necessary for cell migration []. Its expression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer [].Kalirin () promotes the exchange of GDP by GTP and stimulates the activity of specific Rho GTPases []. There are several Kalirin isoforms in humans and mice. Each Kalirin isoform is composed of a unique collection of domains and may have different functions []. In rat, isoforms 1 and 7 are necessary for neuronal development and axonal outgrowth, while isoform 6 is required for dendritic spine formation []. In humans, the major isoform of Kalirin in the adult brain is Kalirin-7, which plays a critical role in spine formation/synaptic plasticity. Kalirin-7 has been linked to neuropsychiatric and neurological diseases such as Alzheimer's, Huntingtin's, ischemic stroke, schizophrenia, depression, and cocaine addiction [, , ].
