Zheng C F, Guan K L
Department of Biological Chemistry, University of Michigan, Ann Arbor 48109.
J Biol Chem. 1993 Aug 5;268(22):16116-9.
The activation of extracellular signal-regulated kinase (ERK) or mitogen-activated protein kinase (MAPK) by a dual specific kinase, MEK (MAPK or ERK kinase), is a critical event in the mitogenic signal transduction pathway. However, little is known about the mechanism of ERK inactivation, which occurs after stimulation. In this report, we demonstrated that a dual specific protein phosphatase, HVH1 (human VH1 phosphatase homolog) whose expression is induced by mitogenic growth factors, specifically inactivates ERK. When several phosphoproteins were tested for recombinant HVH1, only MEK-activated ERK1 was dephosphorylated. HVH1 selectively dephosphorylated threonine and tyrosine residues but not serine residues of the activated ERK1. Inactivation of ERK1 by HVH1 could be reversed by MEK, suggesting that HVH1 dephosphorylates the same residues that are recognized and phosphorylated by MEK. Our results suggest that mitogenic growth factors transiently activate ERK (peak at 5 min followed by a rapid decline) by temporally activating MEK (the on signal) and inducing the expression of HVH phosphatase (the off signal).
由双特异性激酶MEK（丝裂原活化蛋白激酶或细胞外信号调节激酶激酶）激活细胞外信号调节激酶（ERK）或丝裂原活化蛋白激酶（MAPK），是有丝分裂原信号转导途径中的关键事件。然而，对于刺激后发生的ERK失活机制却知之甚少。在本报告中，我们证明了一种双特异性蛋白磷酸酶H VH1（人类VH1磷酸酶同源物），其表达由有丝分裂原生长因子诱导，可特异性地使ERK失活。当对几种磷蛋白进行重组H VH1测试时，只有MEK激活的ERK1被去磷酸化。H VH1选择性地使活化的ERK1的苏氨酸和酪氨酸残基去磷酸化，而不使丝氨酸残基去磷酸化。MEK可逆转H VH1对ERK1的失活作用，这表明H VH1使MEK识别并磷酸化的相同残基去磷酸化。我们的结果表明，有丝分裂原生长因子通过暂时激活MEK（开启信号）并诱导H VH磷酸酶的表达（关闭信号），从而短暂激活ERK（在5分钟时达到峰值，随后迅速下降）。
