Farooq Amjad, Zhou Ming-Ming
Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1677, New York, NY 10029, USA.
Cell Signal. 2004 Jul;16(7):769-79. doi: 10.1016/j.cellsig.2003.12.008.
MAP kinases (MAPKs), which control mitogenic signal transduction in all eukaryotic organisms, are inactivated by dual specificity MAPK phosphatases (DS-MKPs). Recent studies reveal that substrate specificity and enzymatic activity of MKPs are tightly controlled not only by the conserved C-terminal phosphatase domain but also by an N-terminal (NT) kinase-binding domain. Notably, MKPs that consist of a kinase-binding domain and a phosphatase domain exhibit little phosphatase activity in the absence of their physiological substrates. MKP binding to a specific MAPK results in enzymatic activation of the phosphatase in a substrate-induced activation mechanism. This direct coupling of inactivation of an MAPK to activation of an MKP provides a tightly controlled regulation that enables these two key enzymes to keep each other in check, thus guaranteeing the fidelity of signal transduction. This review discusses the recent understanding of structure and regulation of the large family of dual specificity MKPs, which can be divided into four subgroups according to their functional domains and mechanism of substrate recognition and enzymatic regulation. Moreover, detailed comparison of the structural basis between this unique substrate-induced activation mechanism and the common auto-inhibition mechanism is provided.
丝裂原活化蛋白激酶（MAPKs）控制着所有真核生物中的有丝分裂信号转导，它可被双特异性MAPK磷酸酶（DS-MKPs）失活。最近的研究表明，MKPs的底物特异性和酶活性不仅受到保守的C端磷酸酶结构域的严格控制，还受到N端（NT）激酶结合结构域的控制。值得注意的是，由激酶结合结构域和磷酸酶结构域组成的MKPs在没有其生理底物的情况下几乎没有磷酸酶活性。MKP与特定的MAPK结合会在底物诱导的激活机制中导致磷酸酶的酶促激活。MAPK的失活与MKP的激活之间的这种直接耦合提供了一种严格控制的调节方式，使这两种关键酶能够相互制衡，从而保证信号转导的保真度。本综述讨论了对双特异性MKPs大家族的结构和调节的最新认识，根据其功能结构域以及底物识别和酶调节机制，该家族可分为四个亚组。此外，还对这种独特的底物诱导激活机制与常见的自抑制机制之间的结构基础进行了详细比较。
