Dephosphorylation of specific sites in the kinase-specificity sequence domain leads to ubiquitin-mediated degradation of the tyrosine phosphatase STEP.
Dephosphorylation of specific sites in the kinase-specificity sequence domain leads to ubiquitin-mediated degradation of the tyrosine phosphatase STEP.
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DOI：
10.1042/bj20110240
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发表时间：
2011-11-15
期刊：
影响因子：
--
通讯作者：
Paul S
中科院分区：
文献类型：
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作者：
Mukherjee S;Poddar R;Deb I;Paul S
纹状体富集磷酸酶（STEP）是一种非受体酪氨酸磷酸酶，在中枢神经系统的神经元中特异性表达。STEP调节参与突触可塑性和神经元细胞存活的几种效应分子的活性，包括促分裂原活化蛋白激酶（MAPK）、Src家族激酶和N-甲基-D-天冬氨酸（NMDA）受体。STEP在调节这些效应物中的关键作用要求其活性受到严格调节。以前的研究表明，STEP的活性是通过可逆磷酸化激酶相互作用基序（KIM）内的丝氨酸残基，cAMP依赖性蛋白激酶A（PKA）。在这里，我们表明，STEP是内源性磷酸化的激酶特异性序列（KIS）内位于两个额外的网站。ERK和p38 MAPK的基础活性在这两个位点的磷酸化中起重要作用。这两个位点的去磷酸化导致STEP的多聚泛素化和蛋白水解降解。相反，蛋白酶体抑制剂MG-132和环氧霉素可以稳定STEP。STEP的活性形式比非活性形式更容易降解。综上所述，我们的研究结果表明，泛素依赖的蛋白水解可能是一种新的机制，终止STEP的活性不可逆的。
Striatal-enriched phosphatase (STEP) is a non-receptor tyrosine phosphatase that is specifically expressed in neurons of the central nervous system. STEP regulates the activity of several effector molecules involved in synaptic plasticity and neuronal cell survival, including mitogen-activated protein kinases (MAPKs), Src family kinases and N-methyl-D-aspartic acid (NMDA) receptors. The critical role of STEP in regulating these effectors requires that its activity be tightly regulated. Previous studies demonstrated that the activity of STEP is regulated through reversible phosphorylation of a serine residue within the kinase interacting motif (KIM), by cAMP-dependent protein kinase A (PKA). Here we show that STEP is endogenously phosphorylated at two additional sites located within the kinase specificity sequences (KIS). Basal activity of ERK and p38 MAPKs plays an important role in the phosphorylation of these two sites. Dephosphorylation of these two sites leads to poly-ubiquitination and proteolytic degradation of STEP. Conversely, the proteasome inhibitors MG-132 and epoxomicin can stabilize STEP. The active form of STEP is more susceptible to degradation than the inactive form. Taken together our results establish that ubiquitin-dependent proteolysis could be a novel mechanism for terminating the activity of STEP irreversibly.