Mounier C, Lavoie L, Dumas V, Mohammad-Ali K, Wu J, Nantel A, Bergeron J J, Thomas D Y, Posner B I
The Polypeptide Hormone Laboratory, McGill University, Strathcona Building, 3640 University Street, Quebec, H3A 2B2, Montreal, Canada.
Mol Cell Endocrinol. 2001 Feb 28;173(1-2):15-27. doi: 10.1016/s0303-7207(00)00439-1.
Grb10 is a member of a family of adapter proteins that binds to tyrosine-phosphorylated receptors including the insulin receptor kinase (IRK). In this study recombinant adenovirus was used to over-express hGrb10zeta, a new Grb10 isoform, in primary rat hepatocytes and the consequences for insulin signaling were evaluated. Over-expression of hGrb10zeta resulted in 50% inhibition of insulin-stimulated IRK autophosphorylation and activation. Analysis of downstream events showed that hGrb10zeta over-expression specifically inhibits insulin-stimulated glycogen synthase (GS) activity and glycogen synthesis without affecting insulin-induced IRS1/2 phosphorylation, PI3-kinase activation, insulin like growth factor binding protein-1 (IGFBP-1) mRNA expression, and ERK1/2 MAP kinase activity. The classical pathway from PI3-kinase through Akt-PKB/GSK-3 leading to GS activation by insulin was also not affected by hGrb10zeta over-expression. These results indicate that hGrb10zeta inhibits a novel and presently unidentified insulin signaling pathway leading to GS activation in liver.
Grb10是衔接蛋白家族的成员，可与包括胰岛素受体激酶（IRK）在内的酪氨酸磷酸化受体结合。在本研究中，重组腺病毒用于在原代大鼠肝细胞中过表达一种新的Grb10亚型hGrb10ζ，并评估其对胰岛素信号传导的影响。hGrb10ζ的过表达导致胰岛素刺激的IRK自磷酸化和激活受到50%的抑制。对下游事件的分析表明，hGrb10ζ的过表达特异性抑制胰岛素刺激的糖原合酶（GS）活性和糖原合成，而不影响胰岛素诱导的IRS1/2磷酸化、PI3激酶激活、胰岛素样生长因子结合蛋白-1（IGFBP-1）mRNA表达以及ERK1/2丝裂原活化蛋白激酶活性。从PI3激酶经Akt-PKB/GSK-3导致胰岛素激活GS的经典途径也不受hGrb10ζ过表达的影响。这些结果表明，hGrb10ζ抑制了一条新的、目前尚未明确的导致肝脏中GS激活的胰岛素信号通路。
