The GRB10 Gene and Its Splice Variants
GRB10 Interacting Proteins
Human GRB10 has been reported to be associated with receptor tyrosine kinases, nonreceptor tyrosine kinases, and other signaling proteins (Kabir and Kazi 2014). All three human splice variants of GRB10 interact with the insulin receptor (InsR) and negatively regulate insulin signaling (Liu and Roth 1995; Ramos et al. 2006; Yu et al. 2011). The interaction is dependent on insulin stimulation and InsR-pY1322 residue recruits the GRB10-SH2 domain. The insulin-like growth factor 1 receptor (IGF-1R) is another target of GRB10 (Stein et al. 2001). Although GRB10 associates with insulin receptors, no associations were reported with insulin receptor substrates. GRB10 displays a comparatively higher preference for interaction with the InsR than with the IGF-1R (Laviola et al. 1997). The interaction between GRB10 and the insulin receptor is not only mediated through the GRB10-SH2 domain, but also GRB10-BPS domain is involved. InsR and IGF-1R display differential affinity for the SH2 and BPS domains of GRB10, thus explaining the difference in preference for interaction with InsR and IGF-1R (He et al. 1998). The type III receptor tyrosine kinase FLT3 associates with GRB10, and the association is mediated by two phosphotyrosine residues (pY572 and pY793) in FLT3 (Kazi and Rönnstrand 2013). Other GRB10 interacting proteins include the serine/threonine kinases mTORC1, MEK1, RAF1, and ERK1/2 and the tyrosine kinases KDR, TEC, ABL, EGFR, PDGFR, SRC, and FYN etc. (Kabir and Kazi 2014).
GRB10 in Receptor Tyrosine Kinase Signaling
GRB10 is an important component of receptor tyrosine kinase signaling. The presence of multiple domains facilitates interaction between GRB10 and different signaling proteins. GRB10 has been extensively studied with respect to insulin signaling. Current studies suggest that GRB10 is also an essential component of the signaling machinery of other receptor tyrosine kinases. Current studies suggest that depending on the cell type, splice variant, and interaction partners, GRB10 differentially regulates receptor downstream signaling. GRB10 enhances receptor signaling through recruitment of signaling proteins such as GAB1 or PI3K. On the other hand, by recruiting E3 ubiquitin ligases such as NEDD4 or competing with the substrate proteins, for example, IRS1 and IRS2, GRB10 negatively regulates receptor signaling.
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