PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction.
PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction.
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DOI：
10.1158/0008-5472.can-09-3229
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Hou SW;Zhi HY;Pohl N;Loesch M;Qi XM;Li RS;Basir Z;Chen G
蛋白磷酸酶被认为与激酶协调以执行生物学功能，然而这种整合活性的实例仍然缺失。在本报告中，我们鉴定了PTPH 1（蛋白酪氨酸磷酸酶H1）作为p38γ MAPK（丝裂原活化蛋白激酶）的特异性磷酸酶，并通过直接结合证明了它们的协同致癌活性。p38γ是一种Ras效应子，已知其作用不依赖于其磷酸化，首次显示需要其独特的PDZ结合基序来增加Ras转化。酵母双杂交筛选和体外和体内分析进一步鉴定PTPH 1是通过PDZ介导的结合的特异性p38γ磷酸酶。另外的实验表明，PTPH 1本身通过依赖于其p38γ-结合活性的机制在体外和/或小鼠中Ras依赖性恶性肿瘤生长中发挥作用。此外，Ras增加p38γ和PTPH 1蛋白表达，并且在原发性结肠癌组织中存在p38γ和PTPH 1蛋白表达增加的偶联。这些结果揭示了MAPK与其特异性磷酸酶的协同致癌活性，并提示PDZ介导的p38γ/PTPH 1复合物可能是Ras依赖性恶性肿瘤的新靶点。
Protein phosphatases are believed to coordinate with kinases to execute biological functions and examples of such integrated activities however are still missing. In this report, we have identified PTPH1 (protein tyrosine phosphatase H1) as a specific phosphatase for p38γ MAPK (mitogen-activated protein kinase) and demonstrated their cooperative oncogenic activity through direct binding. p38γ, a Ras effector known to act independent of its phosphorylation, was first shown to require its unique PDZ-binding motif to increase Ras transformation. Yeast two-hybrid screening and in vitro and in vivo analysis further identified PTPH1 as a specific p38γ phosphatase through PDZ-mediated binding. Additional experiments showed that PTPH1 itself plays a role in Ras-dependent malignant growth in vitro and/or in mice by mechanism depending on its p38γ-binding activity. Moreover, Ras increases both p38γ and PTPH1 protein expression and there is a coupling of increased p38γ and PTPH1 protein expression in primary colon cancer tissues. These results reveal a coordinative oncogenic activity of a MAPK with its specific phosphatase and suggest that PDZ-mediated p38γ/PTPH1 complex may be a novel target for Ras-dependent malignancies.