Mitogen-activated protein kinase (MAPK) phosphatase 3-mediated cross-talk between MAPKs ERK2 and p38alpha.

ABSTRACT: 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 p38? in vitro and in intact cells. The catalytic constant of the MKP3 reaction for p38? is comparable with that for ERK2. Remarkably, MKP3, ERK2, and phosphorylated p38? can form a stable ternary complex in solution, and the phosphatase activity of MKP3 toward p38? substrate is allosterically regulated by ERK2-MKP3 interaction. This suggests that MKP3 not only controls the activities of ERK2 and p38? but also mediates cross-talk between these two MAPK pathways. The crystal structure of bisphosphorylated p38? has been determined at 2.1 Å resolution. Comparisons between the phosphorylated MAPK structures reveal the molecular basis of MKP3 substrate specificity.

SUBMITTER: Zhang YY 

PROVIDER: S-EPMC3091224 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature