Genua Marco, Pandini Giuseppe, Cassarino Maria Francesca, Messina Rosa Linda, Frasca Francesco
Department of Internal Medicine, University of Catania, Catania, Italy.
Vitam Horm. 2009;80:77-105. doi: 10.1016/S0083-6729(08)00604-3.
Insulin Receptor (IR) and IGF-I receptor (IGF-IR) are homolog but display distinct functions: IR is mainly metabolic, while IGF-IR is mitogenic. However, in some conditions like foetal growth, cancer and diabetes, IR may display some non-metabolic effects like proliferation and migration. The molecular mechanisms underlying this 'functional switch of IR' have been attributed to several factors including overexpression of ligands and receptors, predominant IR isoform expression, preferential recruitment of intracellular substrates. Here, we report that c-Abl, a cytoplasmic tyrosine kinase regulating several signal transduction pathways, is involved in this functional switch of IR. Indeed, c-Abl tyrosine kinase is involved in IR signalling as it shares with IR some substrates like Tub and SORBS1 and is activated upon insulin stimulation. Inhibition of c-Abl tyrosine kinase by STI571 attenuates the effect of insulin on Akt/GSK-3beta phosphorylation and glycogen synthesis, and at the same time, it enhances the effect of insulin on ERK activation, cell proliferation and migration. This effect of STI571 is specific to c-Abl inhibition, because it does not occur in Abl-null cells and is restored in c-Abl-reconstituted cells. Numerous evidences suggest that focal adhesion kinase (FAK) is involved in mediating this c-Abl effect. First, c-Abl tyrosine kinase activation is concomitant with FAK dephosphorylation in response to insulin, whereas c-Abl inhibition is accompanied by FAK phosphorylation in response to insulin, a response similar to that observed with IGF-I. Second, the c-Abl effects on insulin signalling are not observed in cells devoid of FAK (FAK(-/-) cells). Taken together these results suggest that c-Abl activation by insulin, via a modification of FAK response, may play an important role in directing mitogenic versus metabolic insulin receptor signalling.
胰岛素受体（IR）和胰岛素样生长因子-I受体（IGF-IR）是同源的，但具有不同的功能：IR主要参与代谢，而IGF-IR具有促有丝分裂作用。然而，在某些情况下，如胎儿生长、癌症和糖尿病，IR可能会表现出一些非代谢作用，如增殖和迁移。这种“IR功能转换”背后的分子机制归因于几个因素，包括配体和受体的过表达、主要IR异构体的表达、细胞内底物的优先募集。在此，我们报道c-Abl，一种调节多种信号转导途径的细胞质酪氨酸激酶，参与了IR的这种功能转换。事实上，c-Abl酪氨酸激酶参与IR信号传导，因为它与IR共享一些底物，如Tub和SORBS1，并在胰岛素刺激下被激活。STI571抑制c-Abl酪氨酸激酶可减弱胰岛素对Akt/GSK-3β磷酸化和糖原合成的作用，同时增强胰岛素对ERK激活、细胞增殖和迁移的作用。STI571的这种作用是c-Abl抑制所特有的，因为它在Abl基因缺失的细胞中不发生，而在c-Abl重组细胞中恢复。大量证据表明，粘着斑激酶（FAK）参与介导这种c-Abl效应。首先，c-Abl酪氨酸激酶激活与胰岛素刺激下FAK的去磷酸化同时发生，而c-Abl抑制则伴随着胰岛素刺激下FAK的磷酸化，这种反应与IGF-I刺激时观察到的反应相似。其次，在缺乏FAK的细胞（FAK(-/-)细胞）中未观察到c-Abl对胰岛素信号传导的影响。综上所述，这些结果表明，胰岛素通过改变FAK反应激活c-Abl，可能在引导有丝分裂与代谢性胰岛素受体信号传导中起重要作用。
