Grb10: more than a simple adaptor protein.

Abstract

Grb10 is a member of a superfamily of adaptor proteins that includes Grb7 and Grb14. This family of proteins shares a common overall structure, including an N-terminal region harboring a conserved proline-rich motif, a central Pleckstrin homology (PH) domain, a C-terminal Src homology 2 (SH2) domain, and a conserved region located between the PH and the SH2 domains (BPS). Grb10 directly interacts with a number of mitogenic receptor tyrosine kinases including the insulin (IR) and insulin-like growth factor-I (IGF-IR) receptor. Grb10 binds to the regulatory kinase loop of the insulin receptor (IR) via its SH2 and BPS domains. In addition to receptor tyrosine kinases, Grb10 has also been found to interact with non-receptor tyrosine kinases such as Tec and Bcr-Abl, and other cellular signaling molecules such as Raf-1 and the mitogen activated protein (MAP) kinase kinase, MEK. Overexpression of Grb10 has been shown to inhibit or stimulate insulin/IGF-I signaling depending on the expression levels of the specific isoforms, specific cell context, and/or physiologic endpoint. Genetic imprinting of Grb10 has been linked to the congenital disease, Silver-Russell syndrome, which is characterized by pre- and post-natal growth deficiency. This data suggests that Grb10 may function during embryogenesis in regulating insulin/IGF-I signaling as these growth factors play important roles during development. A role of Grb10 as a potent growth inhibitor during was implicated when disruption of the mGrb10 gene in mice resulted in overgrowth of mutant embryos and neonates. Grb10 is expressed in the central nervous system of mice and rats, which suggests that this protein may regulate neuronal insulin signaling and energy metabolism, consistent with its reported role in metabolic insulin action in fat and muscle cells. An important area of future investigation will be to elucidate the mechanism underlying Grb10's ability to regulate peptide hormone action including insulin/IGF-I signaling and to study the physiological role of this adaptor protein in cellular and animal models.