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酪氨酸磷酸酶PTPα的靶向破坏导致激酶Src和Fyn的组成性下调。

Targeted disruption of the tyrosine phosphatase PTPalpha leads to constitutive downregulation of the kinases Src and Fyn.

作者信息

Ponniah S, Wang D Z, Lim K L, Pallen C J

机构信息

Cell Regulation Laboratory, In Vivo Model Systems Unit, Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore, 117609, Republic of Singapore.

出版信息

Curr Biol. 1999 May 20;9(10):535-8. doi: 10.1016/s0960-9822(99)80238-3.

Abstract

A role for the receptor-like protein tyrosine phosphatase alpha (PTPalpha) in regulating the kinase activity of Src family members has been proposed because ectopic expression of PTPalpha enhances the dephosphorylation and activation of Src and Fyn [1] [2] [3]. We have generated mice lacking catalytically active PTPalpha to address the question of whether PTPalpha is a physiological activator of Src and Fyn, and to investigate its other potential functions in the context of the whole animal. Mice homozygous for the targeted PTPalpha allele (PTPalpha-/-) and lacking detectable PTPalpha protein exhibited no gross phenotypic defects. The kinase activities of Src and Fyn were significantly reduced in PTPalpha-/- mouse brain and primary embryonic fibroblasts, and this correlated with enhanced phosphorylation of the carboxy-terminal regulatory Tyr527 of Src in PTPalpha-/- mice. Thus, PTPalpha is a physiological positive regulator of the tyrosine kinases Src and Fyn. Increased tyrosine phosphorylation of several unidentified proteins was also apparent in PTPalpha-/- mouse brain lysates. These may be PTPalpha substrates or downstream signaling proteins. Taken together, the results indicate that PTPalpha has a dual function as a positive and negative regulator of tyrosine phosphorylation events, increasing phosphotyrosyl proteins through activation of Src and Fyn, and directly or indirectly removing tyrosine phosphate from other unidentified proteins.

摘要

有人提出受体样蛋白酪氨酸磷酸酶α(PTPα)在调节Src家族成员的激酶活性中发挥作用,因为PTPα的异位表达增强了Src和Fyn的去磷酸化及激活作用[1][2][3]。我们已培育出缺乏催化活性PTPα的小鼠,以解决PTPα是否为Src和Fyn的生理性激活剂这一问题,并在整体动物背景下研究其其他潜在功能。纯合靶向PTPα等位基因(PTPα-/-)且缺乏可检测到的PTPα蛋白的小鼠未表现出明显的表型缺陷。在PTPα-/-小鼠脑和原代胚胎成纤维细胞中,Src和Fyn的激酶活性显著降低,这与PTPα-/-小鼠中Src羧基末端调节性酪氨酸527的磷酸化增强相关。因此,PTPα是酪氨酸激酶Src和Fyn的生理性正向调节因子。在PTPα-/-小鼠脑裂解物中,几种未鉴定蛋白的酪氨酸磷酸化增加也很明显。这些可能是PTPα的底物或下游信号蛋白。综上所述,结果表明PTPα作为酪氨酸磷酸化事件的正向和负向调节因子具有双重功能,通过激活Src和Fyn增加磷酸酪氨酸蛋白,并直接或间接从其他未鉴定蛋白上去除酪氨酸磷酸。

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