Dickinson Robin J, Keyse Stephen M
Cancer Research UK Stress Response Laboratory, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
J Cell Sci. 2006 Nov 15;119(Pt 22):4607-15. doi: 10.1242/jcs.03266.
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 non-catalytic 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.
在哺乳动物中，一个由10种双特异性（苏氨酸/酪氨酸）蛋白磷酸酶组成的结构独特的亚家族负责有丝分裂原活化蛋白激酶（MAPK）家族成员的调节性去磷酸化和失活。这些MAPK磷酸酶（MKP）通过位于蛋白质N端非催化结构域内的模块化激酶相互作用基序（KIM）与它们的底物特异性相互作用。此外，MAPK结合通常伴随着C端催化结构域的酶促激活，从而确保作用的特异性。尽管我们了解MKP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了解得要少得多。然而，最近使用一系列模型系统的研究已经开始揭示MKP在多种生理背景下决定MAPK信号传导结果方面的重要非冗余作用。这些作用包括发育、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亚细胞MKP活性的限制以及通过多种MAPK途径的信号水平变化。
