ABSTRACT
Growth factor receptor binding protein 10 (Grb-10) has been identified as a cellular partner of a number of receptor tyrosine kinases which is compatible with a role as a mitogenic signaling mediator. At least six variants have been identified within the Grb-10 gene, a proposed candidate gene for human Silver-Russel syndrome located on chromosome 7 (human) or 11 (mouse), the gene is oppositely imprinted in both species. The Grb-10 isoforms are members of the Grb-7 family of signaling mediators which include Grb-7, Grb-14, and Caenorhabditis elegans MIG-10. All mammalian members of this family share a domain structure of an amino terminal (proline) Pro-rich putative SH3 domain binding region, a homology domain with MIG-10 (GM), a pleckstrin homology region (PH), a carboxyl terminal Src homology 2 (SH2) domain, and a newly defined receptor binding region between the PH and the SH2 domains (BPS). Various Grb-10 isoforms have been identified as cellular partners of the insulin receptor (IR) and insulinlike growth factor-I (IGF-I) receptor; a preference for the IR has been suggested for one isoform. A role of Grb-10 has been implicated in mitogenesis (including malignant cell transformation), positive or negative, depending on the specific cellular context in response to insulin or IGF-I. The underlying signaling mechanism appears to involve phosphatidyl inositol 3′ kinase (PI3K), p60 GAP-associated protein, ubiquitin ligase Nedd 4, the mitogen-activated protein kinase (MAPK) signaling cascade, and other pathways/ mediators including tyrosine kinases such as Jak2, Tec, and the oncogenes Src, Fyn and Bcr-Abl. A role in mitogenesis and in insulin action has also been implicated for the related Grb-7 and Grb-14. Evidence for a role of Grb-10 in insulin metabolic actions is emerging through the observed effect on insulin-stimulated glucose uptake and glycogen synthesis.
