Diverse physiological functions for dual-specificity MAP kinase phosphatases
Diverse physiological functions for dual-specificity MAP kinase phosphatases
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DOI：
10.1242/jcs.03266
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发表时间：
2006-11-15
影响因子：
4
通讯作者：
Keyse, Stephen M.
中科院分区：
文献类型：
--
作者：
Dickinson, Robin J.;Keyse, Stephen M.
双特异性（Thr/Tyr）蛋白磷酸酶是一个结构独特的蛋白磷酸酶亚家族，在哺乳动物中负责丝裂原活化蛋白激酶（MAPK）家族成员的去磷酸化和失活。这些MAPK磷酸酶（MKPs）通过位于蛋白质N-末端非催化结构域内的模块化激酶相互作用基序（KIM）与其底物特异性相互作用。此外，MAPK结合通常伴随着C-末端催化结构域的酶促活化，从而确保作用的特异性。尽管我们知道MKPs催化机制的生化和结构基础，但我们对它们在哺乳动物细胞和组织中的调节和生理功能知之甚少。然而，最近的研究采用了一系列的模型系统已经开始揭示必要的非冗余的作用MKPs在确定的结果MAPK信号在各种生理环境。这些包括发育，免疫系统功能，代谢稳态和细胞应激反应的调节。有趣的是，这些功能可能反映了受限的亚细胞MKP活性和通过多种MAPK途径的信号传导水平的变化。
A structurally distinct subfamily of ten dual-specificity (Thr/Tyr) protein phosphatases is responsible for the regulated dephosphorylation and inactivation of mitogen-activated protein kinase ( MAPK) family members in mammals. These MAPK phosphatases (MKPs) interact specifically with their substrates through a modular kinase-interaction motif (KIM) located within the N-terminal noncatalytic domain of the protein. In addition, MAPK binding is often accompanied by enzymatic activation of the C-terminal catalytic domain, thus ensuring specificity of action. Despite our knowledge of the biochemical and structural basis for the catalytic mechanism of the MKPs, we know much less about their regulation and physiological functions in mammalian cells and tissues. However, recent studies employing a range of model systems have begun to reveal essential non-redundant roles for the MKPs in determining the outcome of MAPK signalling in a variety of physiological contexts. These include development, immune system function, metabolic homeostasis and the regulation of cellular stress responses. Interestingly, these functions may reflect both restricted subcellular MKP activity and changes in the levels of signalling through multiple MAPK pathways.