Growth factor receptor-bound protein 2 (Grb2) is an SH2 and SH3 domain-containing adaptor protein that links receptor tyrosine kinases to Ras signalling []. Grb2 interacts with the cytoplasmic tyrosine kinase ACK1 (activated Cdc42-associated kinase 1) and mediates its interaction with other receptor tyrosine kinases []. ACK1 is implicated in metastatic behaviour, cell spreading and migration, and epidermal growth factor receptor (EGFR) signalling [].
GRB2 (growth factor receptor-bound protein 2) is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis and angiogenesis []. In lymphocytes, GRB2 is associated with antigen receptor signaling components []. GRB2 contains an N-terminal SH3 domain, a central SH2 domain and a C-terminal SH3 domain. This entry represents the SH3 domain found at the N terminus of GRB2. This SH3 domain has been found to bind to Sos and Sos-derived proline-rich peptides [].
GRB2 (growth factor receptor-bound protein 2) is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis and angiogenesis []. In lymphocytes, GRB2 is associated with antigen receptor signaling components []. GRB2 contains an N-terminal SH3 domain, a central SH2 domain and a C-terminal SH3 domain. This entry represents the SH3 domain found at the C terminus of GRB2. This SH3 domain has been found to bind to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C terminus of FGRF2 [, ].
This entry includes THEMIS1/2/3 from animals. THEMIS1 and THEMIS2 are restricted to B and myeloid cells, and the more distantly related THEMIS3 is expressed in the large and small intestine. THEMIS is involved in the early TCR (T-cell antigen receptor) signal transduction and thymocyte selection []. It is recruited to LAT through GRB2 association and LAT phosphotyrosine GRB2 binding sites []. THEMIS contains CABIT modules that bind directly to the SHP-1 PTP (protein tyrosine phosphatase) domain and inhibit SHP-1 PTP activity by promoting or stabilizing oxidation of the catalytic cysteine [].
This entry includes lymphocyte antigen 6 complex locus protein G6d and G6f, which are encoded in the MHC (major histocompatibility complex). Human and mouse G6d was found to be GPI-anchored cell surface proteins, highly expressed at the leading edges of cells, on filopodia, which are normally involved in cell adhesion and migration. The human G6f protein may play a role in the downstream signal transduction pathways involving GRB2 and GRB7, including the Ras-MAP kinase pathway [].
Growth factor receptor-bound protein 2 (Grb2) is an SH2 and SH3 domain-containing adaptor protein that links receptor tyrosine kinases to Ras signalling []. Grb2 interacts with the cytoplasmic tyrosine kinase ACK1 (activated Cdc42-associated kinase 1) and mediates its interaction with other receptor tyrosine kinases []. ACK1 is implicated in metastatic behaviour, cell spreading and migration, and epidermal growth factor receptor (EGFR) signalling [].Human GRAP and its Drosophila homologue, downstream of receptor kinase (drk), have been shown to have a function in hearing [].This entry includes a group of adapter proteins including Grb2, GRAP and GRAPL from humans. This entry also includes Sem-5 from Caenorhabditis elegans. Sem-5 is an adapter protein which modulates signaling mediated by several receptor tyrosine kinases such as egl-15 and let-23 probably acting upstream of let-60/ras [, ].
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.
Protein GAPT (also known as Growth-factor Receptor-Bound protein 2 (GRB2)-binding adaptor protein, transmembrane) belongs to a class of transmembrane (TM) adaptor proteins that couple antigen receptor engagement to downstream signalling cascades in lymphocytes []. Expressed in B cells and myeloid cells, GAPT negatively regulates B-cell proliferation following stimulation through the B-cell receptor; it may also play an important role in the proper maintenance of marginal zone B-cells [].GAPT has an extracellular domain, a TM domain, and a cytoplasmic tail with multiple GRB2-binding motifs; it constitutively associates with GRB2 SH3 domains via a proline-rich region []. Its cytosolic domain contains 7 tyrosine residues (4 of them within GRB2-binding motifs), and 2 cysteines in the juxta-membrane region, which may be palmitoylated [].
The Dok family adapters are phosphorylated by different protein tyrosine kinases. Dok proteins are involved in processes such as modulation of cell differentiation and proliferation, as well as in control of the cell spreading and migration The Dok protein contains an N-terminal pleckstrin homology (PH) domain followed by a central phosphotyrosine binding (PTB) domain, which has a PH-like fold, and a proline- and tyrosine-rich C-terminal tail. The PH domain binds to acidic phospholids and localizes proteins to the plasma membrane, while the PTB domain mediates protein-protein interactions by binding to phosphotyrosine-containing motifs [].There are 7 mammalian Dok member (Dok-1 to 7). Dok-1 and Dok-2 act as negative regulators of the Ras-Erk pathway downstream of many immunoreceptor-mediated signaling systems, and it is believed that recruitment of p120 rasGAP by Dok-1 and Dok-2 is critical to their negative regulation []. Dok-3 is a negative regulator of the activation of JNK and mobilization of Ca2+ in B-cell receptor-mediated signaling, interacting with SHIP-1 and Grb2 [].This entry represents the PTB domain of Dok1/2/3.
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 [].
Tom1 (target of Myb 1) and its related proteins (Tom1L1 and Tom1L2) constitute a protein family and share an N-terminal VHS (Vps27p/Hrs/Stam) domain followed by a GAT (GGA and Tom1) domain.VHS domains are found at the N termini of select proteins involved in intracellular membrane trafficking and are often localized to membranes. The three dimensional structure of human TOM1 VHS domain reveals eight helices arranged in a superhelix. The surface of the domain has two main features: (1) a basic patch on one side due to several conserved positively charged residues on helix 3 and (2) a negatively charged ridge on the opposite side, formed by residues on helix 2 []. The basic patch is thought to mediate membrane binding.It was demonstrated that the GAT domain of both Tom1 and Tom1L1 binds ubiquitin, suggesting that these proteins might participate in the sorting of ubiquitinated proteins into multivesicular bodies (MVB) []. Moreover, Tom1L1 interacts with members of the MVB sorting machinery. Specifically, the VHS domain of Tom1L1 interacts with Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate), whereas a PTAP motif, located between the VHS and GAT domains of Tom1L1, is responsible for binding to TSG101 (tumour susceptibility gene 101). Myc epitope-tagged Tom1L1 is recruited to endosomes following Hrs expression. In addition, Tom1L1 possesses several tyrosine motifs at the C-terminal region that mediate interactions with members of the Src family kinases and other signalling proteins such as Grb2 and p85. Expression of a constitutively active form of Fyn kinase promotes the recruitment of Tom1L1 to enlarged endosomes. It is proposed that Tom1L1 could act as an intermediary between the signalling and degradative pathways [].Over expression of Tom1 suppresses activation of the transcription factors NF-kappaB and AP-1, induced by either IL-1beta or tumour necrosis factor (TNF)-alpha, and the VHS domain of Tom1 is indispensable for this suppressive activity. This suggests that Tom1 is a common negative regulator of signalling pathways induced by IL-1beta and TNF-alpha [].
