The Grb7 (growth factor receptor-bound 7) family includes Grb7, Grb10, and Grb14. These are adapter proteins mediating signal transduction from multiple cell surface receptors to diverse downstream pathways. They are composed of an N-terminal proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a PIR (phosphorylated insulin receptor interacting region) domain (also known as the family-specific BPS region), and a C-terminal SH2 domain []. Grb10 inhibits insulin receptor kinase activity and mediates insulin-stimulated degradation of the insulin receptor []. It binds to the regulatory kinase loop of the insulin receptor (IR) via its SH2 and BPS domains []. Grb10 is directly phosphorylated by mTORC1 and may participate in a feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways [].
This entry represents the SH2 domain of Grb10.The Grb7 (growth factor receptor-bound 7) family includes Grb7, Grb10, and Grb14. These are adapter proteins mediating signal transduction from multiple cell surface receptors to diverse downstream pathways. They are composed of an N-terminal proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a PIR (phosphorylated insulin receptor interacting region) domain (also known as the family-specific BPS region), and a C-terminal SH2 domain []. Grb10 inhibits insulin receptor kinase activity and mediates insulin-stimulated degradation of the insulin receptor []. It binds to the regulatory kinase loop of the insulin receptor (IR) via its SH2 and BPS domains []. Grb10 is directly phosphorylated by mTORC1 and may participate in a feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways [].
Proteins in this entry consist of a Ras-associated (RA) domain, a PH domain, a family-specific BPS region, and a C-terminal SH2 domain. Grb7, Grb10 and Grb14 are paralogues that are also present in this entry []. These adapter proteins bind a variety of receptor tyrosine kinases, including the insulin and insulin-like growth factor-1 (IGF1) receptors. Grb10 and Grb14 are important tissue-specific negative regulators of insulin and IGF1 signaling based and may contribute to type 2 (non-insulin-dependent) diabetes in humans. RA-PH function as a single structural unit and is dimerized via a helical extension of the PH domain. The PH domain here are proposed to bind phosphoinositides non-cannonically and are unlikely to bind an activated GTPase []. This entry also includes APBB1IP (also known as RIAM), which functions in the signal transduction from Ras activation to actin cytoskeletal remodelling [].
This entry represents the SAM (sterile alpha motif) domain of the EphB1 receptors. This domain, located in the cytoplasmic region of EphB1, is a potential C-terminal protein-protein interaction domain. In human vascular endothelial cells, it appears to mediate cell-cell initiated signal transduction via the binding of the adaptor protein GRB10 (growth factor) through its SH2 domain to a conserved tyrosine that is phosphorylated []. EphB1 receptors play a role in neurogenesis, in particular in regulation of proliferation and migration of neural progenitors in the hippocampus and in corneal neovascularization []; they are involved in converting the crossed retinal projection to ipsilateral retinal projection []. They may be potential targets in angiogenesis-related disorders [].
Amyloid beta A4 precursor protein-binding family B member 1-interacting protein (APBB1IP) consists of a Ras-associated (RA) domain, a PH domain, a family-specific BPS region, and a C-terminal SH2 domain. Grb7, Grb10 and Grb14 are paralogues that are also present in this entry []. These adapter proteins bind a variety of receptor tyrosine kinases, including the insulin and insulin-like growth factor-1 (IGF1) receptors. Grb10 and Grb14 are important tissue-specific negative regulators of insulin and IGF1 signaling based and may contribute to type 2 (non-insulin-dependent) diabetes in humans. RA-PH function as a single structural unit and is dimerized via a helical extension of the PH domain. The PH domain here are proposed to bind phosphoinositides non-cannonically and are unlikely to bind an activated GTPase []. The tandem RA-PH domains are present in a second adapter-protein family, MRL proteins, Caenorhabditis elegansprotein MIG-1012, the mammalian proteins RIAM and lamellipodin and the Drosophila melanogasterprotein Pico12, all of which are Ena/VASP-binding proteins involved in actin-cytoskeleton rearrangement.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. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane []. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.
