Serum alpha 2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase level.
Serum alpha 2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase level.
复制标题
DOI：
10.1210/mend.7.11.7906861
复制
发表时间：
1993-11
影响因子：
--
通讯作者：
P. Srinivas;A. S. Wagner;L. V. Reddy;D. D. Deutsch-D.;M. A. León;A. Goustin;G. Grunberger
中科院分区：
文献类型：
--
作者：
P. Srinivas;A. S. Wagner;L. V. Reddy;D. D. Deutsch-D.;M. A. León;A. Goustin;G. Grunberger
胰岛素受体（IR）的胰岛素依赖性酪氨酸激酶活性（TKA）在胰岛素信号传导中起重要作用。因此，IR-TKA的失调可能是胰岛素抵抗状态的重要因素。已经描述了作为IR-TK抑制剂的磷酸化大鼠肝糖蛋白（pp 63）。为了寻找pp 63的人类同源物，我们从人肝λ gt 11 cDNA文库中分离了一个cDNA克隆。DNA序列分析揭示了与编码血清蛋白α 2-Heremans Scmid-glycoprotein（α 2 HSG）的人基因AHSG的mRNA产物的同一性，该蛋白具有迄今未知的生理功能。北方印迹分析表明人肝脏和HepG 2肝癌细胞中存在1.8千碱基的mRNA。从人血清中纯化的α 2 HSG在体外和体内特异性抑制胰岛素刺激的IR自磷酸化以及外源性底物酪氨酸磷酸化。α 2 HSG还抑制胰岛素诱导的IRS-1的酪氨酸磷酸化和IRS-1与H-35肝癌细胞中磷脂酰肌醇-3激酶的p85亚基的结合。α 2 HSG抑制胰岛素依赖性有丝分裂，但不影响胰岛素刺激的代谢酶酪氨酸氨基转移酶诱导。α 2 HSG不与胰岛素竞争结合IR。最后，α 2 HSG的作用对IR-TK具有特异性;其作用不延伸至胰岛素样生长因子-I刺激的TKA。我们的研究结果使我们能够分配人α 2 HSG的生化功能，即在IR-TK水平调节胰岛素作用。
The insulin-dependent tyrosine kinase activity (TKA) of the insulin receptor (IR) plays an essential role in insulin signaling. Thus, dysregulation of IR-TKA might be an important element in the states of insulin resistance. A phosphorylated rat hepatic glycoprotein (pp63) acting as an inhibitor of IR-TK has been described. In search of the human homolog of pp63, we isolated a cDNA clone from a human liver lambda gt11 cDNA library. DNA sequence analysis reveals identity with the mRNA product of a human gene AHSG encoding a serum protein, alpha 2-Heremans Scmid-glycoprotein (alpha 2HSG), with heretofore unknown physiological function. Northern blot analysis demonstrates a 1.8-kilobase mRNA in human liver and HepG2 hepatoma cells. alpha 2HSG, purified from human serum, specifically inhibits insulin-stimulated IR autophosphorylation in vitro and in vivo as well as exogenous substrate tyrosine phosphorylation. alpha 2HSG also inhibits both insulin-induced tyrosine phosphorylation of IRS-1 and the association of IRS-1 with the p85 subunit of phosphatidylinositol-3 kinase in H-35 hepatoma cells. alpha 2HSG inhibits insulin-dependent mitogenesis, but does not affect insulin-stimulated induction of the metabolic enzyme tyrosine aminotransferase. alpha 2HSG does not compete with insulin for binding to IR. Finally, the action of alpha 2HSG is specific toward the IR-TK; its effect does not extend to insulin-like growth factor-I-stimulated TKA. Our results allow us to assign a biochemical function for human alpha 2HSG, namely regulation of insulin action at the IR-TK level.