Insulin receptor protein-tyrosine phosphatases. Leukocyte common antigen-related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain.
Insulin receptor protein-tyrosine phosphatases. Leukocyte common antigen-related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain.
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DOI：
10.1016/s0021-9258(19)49639-7
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发表时间：
1992-07
期刊：
影响因子：
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通讯作者：
N. Hashimoto;E. Feener;W. R. Zhang;B. Goldstein
中科院分区：
文献类型：
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作者：
N. Hashimoto;E. Feener;W. R. Zhang;B. Goldstein
许多蛋白酪氨酸磷酸酶（PTPases）已显示在体外使胰岛素受体去磷酸化;然而，尚不清楚是否有任何单个PTPases对调节其内在酪氨酸激酶活性的受体的某些磷酸酪氨酸残基具有特异性。我们评估了胰岛素敏感大鼠组织中表达的三种候选酶对胰岛素受体激酶的失活，包括受体样PTPases LAR和LRP以及细胞内酶PTPase 1B。纯化的胰岛素受体通过胰岛素和受体去磷酸化活化，并且在与来自大肠杆菌表达系统的重组PTPases孵育后定量激酶活性。当与整体受体去磷酸化水平相关时，LAR使受体激酶失活的速度分别比PTPase 1B或LRP快3.1倍和2.1倍（p <0.03）。为了评估这些效应是否与受体β亚基的调节（Tyr-1150）结构域的优先去磷酸化有关，我们对PTPases去磷酸化后的胰岛素受体β亚基进行了胰蛋白酶图谱分析。相对于32 P从受体C-末端位点的初始损失率，LAR使Tris-磷酸化的Tyr-1150结构域去磷酸化的速度分别比PTPase 1B或LRP快3.5倍和3.7倍（p <0.01）。LAR对胰岛素受体激酶的加速失活及其对调节磷酸酪氨酸残基的相对偏好进一步支持了这种跨膜蛋白在完整细胞中胰岛素受体的生理调节中的潜在作用。
A number of protein-tyrosine phosphatase(s) (PTPases) have been shown to dephosphorylate the insulin receptor in vitro; however, it is not known whether any individual PTPase has specificity for certain phosphotyrosine residues of the receptor that regulate its intrinsic tyrosine kinase activity. We evaluated the deactivation of the insulin receptor kinase by three candidate enzymes that are expressed in insulin-sensitive rat tissues, including the receptor-like PTPases LAR and LRP, and the intracellular enzyme, PTPase1B. Purified insulin receptors were activated by insulin and receptor dephosphorylation, and kinase activity was quantitated after incubation with recombinant PTPases from an Escherichia coli expression system. When related to the level of overall receptor dephosphorylation, LAR deactivated the receptor kinase 3.1 and 2.1 times more rapidly than either PTPase1B or LRP, respectively (p less than 0.03). To assess whether these effects were associated with preferential dephosphorylation of the regulatory (Tyr-1150) domain of the receptor beta-subunit, we performed tryptic mapping of the insulin receptor beta-subunit after dephosphorylation by PTPases. Relative to the rate of initial loss of 32P from receptor C-terminal sites, LAR dephosphorylated the Tris-phosphorylated Tyr-1150 domain 3.5 and 3.7 times more rapidly than either PTPase1B or LRP, respectively (p less than 0.01). The accelerated deactivation of the insulin receptor kinase by LAR and its relative preference for regulatory phosphotyrosine residues further support a potential role for this transmembrane PTPase in the physiological regulation of insulin receptors in intact cells.