Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway
Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway
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DOI：
10.1074/jbc.m202149200
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发表时间：
2002-08-16
影响因子：
4.8
通讯作者：
Ullrich, A
中科院分区：
文献类型：
--
作者：
Buschbeck, M;Eickhoff, J;Ullrich, A
丝裂原活化蛋白激酶（MAPK）激活的持续时间和幅度指定信号的身份，从而允许通过相同的激酶级联调节不同的细胞功能。因此，MAPK活性的紧密和精细调节对于特定细胞应答的定义至关重要。我们研究了酪氨酸特异性磷酸酶（PTPs）在ERK 5调节中的作用。尽管其结构独特，但ERK 5类似于其他MAPK通过其活化基序中的苏氨酸和酪氨酸残基的双重磷酸化而被活化。在这项研究中，我们集中在PTP-SL，一个激酶相互作用的基序包含PTP，是否以及如何可能参与下调ERK 5信号。我们发现，这两种蛋白质直接相互作用，在体外和完整的细胞，导致其酶活性的相互调节。PTP-SL是ERK 5的底物，与激酶结合不依赖于磷酸化，增强其催化磷酸酶活性。另一方面，与PTP-SL的相互作用不仅下调内源性ERK 5活性，而且有效地阻止ERK 5向细胞核的转运。这些发现表明PTP-SL对ERK 5通路和细胞的相应下游反应的直接调节影响。
The duration and the magnitude of mitogen-activated protein kinase (MAPK) activation specifies signal identity and thus allows the regulation of diverse cellular functions by the same kinase cascade. A tight and finely tuned regulation of MAPK activity is therefore critical for the definition of a specific cellular response. We investigated the role of tyrosine-specific phosphatases (PTPs) in the regulation of ERK5. Although unique in its structure, ERK5 is activated in analogy to other MAPKs by dual phosphorylation of threonine and tyrosine residues in its activation motif. In this study we concentrated on whether and how PTP-SL, a kinase-interacting motif-containing PTP, might be involved in the down-regulation of the ERK5 signal. We found that both proteins interact directly with each other in vitro and in intact cells, resulting in mutual modulation of their enzymatic activities. PTP-SL is a substrate of ERK5 and independent of phosphorylation binding to the kinase enhances its catalytic phosphatase activity. On the other hand, interaction with PTP-SL not only down-regulates endogenous ERK5 activity but also effectively impedes the translocation of ERK5 to the nucleus. These findings indicate a direct regulatory influence of PTP-SL on the ERK5 pathway and corresponding downstream responses of the cell.