[Control of insulin signalisation and action by the Grb14 protein]

The action of insulin on metabolism and cell growth is mediated by a specific receptor tyrosine kinase, which, through phosphorylation of several substrates, triggers the activation of two major signaling pathways, the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway and the Ras/extracellular signal-regulated kinase (ERK) pathway. Insulin-induced activation of the receptor and downstream signaling is also subjected to a negative feedback control involving several mechanisms, among which the interaction of the insulin receptor and its substrates with inhibitory proteins. After summarizing the major mechanisms underlying the activation and attenuation of insulin signaling, this review focuses on its control by the Grb14 adaptor protein. Grb14 has been identif-ied as an inhibitor of insulin signaling and action, and is involved in insulin resistance associated with type 2 diabetes and obesity. Studies on the molecular mechanism of action of Grb14 have shown that, through interaction with the activated insulin receptor, Grb14 inhibits its catalytic activity and the activation of downstream signaling. However, the consequences of Grb14 gene invalidation are complex and tissue-specific, and some effects of Grb14 on insulin signaling appear to be linked to its interaction with effector proteins downstream the insulin receptor. Pharmacological inhibition of Grb14 should allow to enhance insulin sensitivity and improve energy homeostasis in insulin-resistant states.