Roth R A, Liu F, Chin J E
Department of Molecular Pharmacology, Stanford University School of Medicine, CA 94305.
Horm Res. 1994;41 Suppl 2:51-5. doi: 10.1159/000183961.
The insulin receptor tyrosine kinase is required for insulin to elicit subsequent biological signalling. Recent studies have identified several endogenous substrates of the insulin receptor kinase, including one called insulin receptor substrate 1 (IRS-1). Tyrosine phosphorylation of this substrate results in its being bound by various proteins containing src homology 2 (SH2) sites, including a phosphatidylinositol 3-kinase and a ras activator complex containing GRB2 and son of sevenless (SOS) 1. Decreases in the insulin receptor tyrosine kinase activity have been observed in various insulin-resistant states, such as non-insulin-dependent diabetes mellitus. A model of insulin resistance has recently been described in which the insulin receptor is expressed in Chinese hamster ovary cells along with the phospholipid- and calcium-activated serine/threonine kinase called protein kinase C. In this model system, activation of protein kinase C is shown to interfere with insulin receptor signalling by inhibiting tyrosine phosphorylation of IRS-1 and its subsequent binding by phosphatidylinositol 3-kinase. Such a model system may be further utilized to determine the detailed biochemical basis for insulin resistance.
胰岛素引发后续生物信号传导需要胰岛素受体酪氨酸激酶。最近的研究已鉴定出胰岛素受体激酶的几种内源性底物，包括一种名为胰岛素受体底物1（IRS-1）的底物。该底物的酪氨酸磷酸化导致其被各种含有src同源2（SH2）结构域的蛋白质结合，包括磷脂酰肌醇3-激酶以及一种含有GRB2和七号染色体失活蛋白（SOS）1的ras激活复合物。在各种胰岛素抵抗状态下，如非胰岛素依赖型糖尿病，已观察到胰岛素受体酪氨酸激酶活性降低。最近描述了一种胰岛素抵抗模型，其中胰岛素受体与称为蛋白激酶C的磷脂和钙激活的丝氨酸/苏氨酸激酶一起在中国仓鼠卵巢细胞中表达。在该模型系统中，蛋白激酶C的激活显示通过抑制IRS-1的酪氨酸磷酸化及其随后被磷脂酰肌醇3-激酶的结合来干扰胰岛素受体信号传导。这样的模型系统可进一步用于确定胰岛素抵抗的详细生化基础。
