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Regulation of insulin and type 1 insulin‐like growth factor signaling and action by the G rb10/14 and SH 2 B 1/ B 2 adaptor proteins
Author(s) -
Desbuquois Bernard,
Carré Nadège,
Burnol AnneFrançoise
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12080
Subject(s) - insulin receptor , grb10 , insulin receptor substrate , insulin , irs1 , irs2 , receptor , microbiology and biotechnology , insulin like growth factor , signal transduction , biology , growth factor , receptor tyrosine kinase , insulin resistance , insulin like growth factor 1 receptor , signal transducing adaptor protein , tyrosine kinase , endocrinology , biochemistry
The effects of insulin and type 1 insulin‐like growth factor ( IGF –1) on metabolism, growth and survival are mediated by their association with specific receptor tyrosine kinases, which results in both receptor and substrate phosphorylation. Phosphotyrosine residues on receptors and substrates provide docking sites for signaling proteins containing SH 2 (Src homology 2) domains, including molecular adaptors. This review focuses on the regulation of insulin/ IGF –1 signaling and action by two adaptor families with a similar domain organization: the growth factor receptor‐bound proteins Grb7/10/14 and the SH 2B proteins. Both Grb10/14 and SH 2 B 1/ B 2 associate with the activation loop of insulin/ IGF –1 receptors through their SH 2 domains, but association of G rb10/14 also involves their unique BPS domain. Consistent with Grb14 binding as a pseudosubstrate to the kinase active site, insulin/ IGF ‐induced activation of receptors and downstream signaling pathways in cultured cells is inhibited by G rb10/14 adaptors, but is potentiated by SH 2 B 1/ B 2 adaptors. Accordingly, G rb10 and G rb14 knockout mice show improved insulin/ IGF sensitivity in vivo , and, for G rb10, overgrowth and increased skeketal muscle and pancreatic β–cell mass. Conversely, SH 2 B 1‐depleted mice display insulin and IGF –1 resistance, with peripheral depletion leading to reduced adiposity and neuronal depletion leading to obesity through associated leptin resistance. G rb10/14 and SH 2 B 1 adaptors also modulate insulin/ IGF –1 action by interacting with signaling components downstream of receptors and exert several tissue‐specific effects. The identification of G rb10/14 and SH 2 B 1 as physiological regulators of insulin signaling and action, together with observations that variants at their gene loci are associated with obesity and/or insulin resistance, highlight them as potential therapeutic targets for these conditions.