Ministry of Education Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
J Biol Chem. 2011 May 6;286(18):16150-62. doi: 10.1074/jbc.M110.203786. Epub 2011 Mar 16.
MAPK phosphatase 3 (MKP3) is highly specific for ERK1/2 inactivation via dephosphorylation of both phosphotyrosine and phosphothreonine critical for enzymatic activation. Here, we show that MKP3 is able to effectively dephosphorylate the phosphotyrosine, but not phosphothreonine, in the activation loop of p38α in vitro and in intact cells. The catalytic constant of the MKP3 reaction for p38α is comparable with that for ERK2. Remarkably, MKP3, ERK2, and phosphorylated p38α can form a stable ternary complex in solution, and the phosphatase activity of MKP3 toward p38α substrate is allosterically regulated by ERK2-MKP3 interaction. This suggests that MKP3 not only controls the activities of ERK2 and p38α but also mediates cross-talk between these two MAPK pathways. The crystal structure of bisphosphorylated p38α has been determined at 2.1 Å resolution. Comparisons between the phosphorylated MAPK structures reveal the molecular basis of MKP3 substrate specificity.
丝裂原活化蛋白激酶磷酸酶 3（MKP3）通过去磷酸化 ERK1/2 激活所必需的两个关键磷酸酪氨酸和磷酸苏氨酸，高度特异性地使 ERK1/2 失活。在这里，我们表明 MKP3 能够有效地在体外和完整细胞中使 p38α 的激活环中的磷酸苏氨酸而不是磷酸酪氨酸去磷酸化。MKP3 反应对 p38α 的催化常数与 ERK2 的催化常数相当。值得注意的是，MKP3、ERK2 和磷酸化的 p38α 可以在溶液中形成稳定的三元复合物，并且 ERK2-MKP3 相互作用对 MKP3 对 p38α 底物的磷酸酶活性进行别构调节。这表明 MKP3 不仅控制 ERK2 和 p38α 的活性，而且还介导这两条 MAPK 途径之间的串扰。双磷酸化 p38α 的晶体结构已在 2.1 Å 分辨率下确定。磷酸化 MAPK 结构之间的比较揭示了 MKP3 底物特异性的分子基础。
