Distinct Cellular Functions of MK2
Open Access
- 1 July 2002
- journal article
- research article
- Published by Taylor & Francis in Molecular and Cellular Biology
- Vol. 22 (13), 4827-4835
- https://doi.org/10.1128/mcb.22.13.4827-4835.2002
Abstract
Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) is activated upon stress by p38 MAPKα and -β, which bind to a basic docking motif in the C terminus of MK2 and which subsequently phosphorylate its regulatory sites. As a result of activation MK2 is exported from the nucleus to the cytoplasm and cotransports active p38 MAPK to this compartment. Here we show that the amount of p38 MAPK is significantly reduced in cells and tissues lacking MK2, indicating a stabilizing effect of MK2 for p38. Using a murine knockout model, we have previously shown that elimination of MK2 leads to a dramatic reduction of tumor necrosis factor (TNF) production in response to lipopolysaccharide. To further elucidate the role of MK2 in p38 MAPK stabilization and in TNF biosynthesis, we analyzed the ability of two MK2 isoforms and several MK2 mutants to restore both p38 MAPK protein levels and TNF biosynthesis in macrophages. We show that MK2 stabilizes p38 MAPK through its C terminus and that MK2 catalytic activity does not contribute to this stabilization. Importantly, we demonstrate that stabilizing p38 MAPK does not restore TNF biosynthesis. TNF biosynthesis is only restored with MK2 catalytic activity. We further show that, in MK2-deficient macrophages, formation of filopodia in response to extracellular stimuli is reduced. In addition, migration of MK2-deficient mouse embryonic fibroblasts (MEFs) and smooth muscle cells on fibronectin is dramatically reduced. Interestingly, reintroducing catalytic MK2 activity into MEFs alone is not sufficient to revert the migratory phenotype of these cells. In addition to catalytic activity, the proline-rich N-terminal region is necessary for rescuing the migratory phenotype. These data indicate that catalytic activity of MK2 is required for both cytokine production and cell migration. However, the proline-rich MK2 N terminus provides a distinct role restricted to cell migration.Keywords
This publication has 24 references indexed in Scilit:
- α2 Integrin Subunit Cytoplasmic Domain-dependent Cellular Migration Requires p38 MAPKJournal of Biological Chemistry, 2001
- A conserved docking motif in MAP kinases common to substrates, activators and regulatorsNature Cell Biology, 2000
- The Role of Thin Filopodia in Motility and MorphogenesisExperimental Cell Research, 1999
- A Role for p38MAPK/HSP27 Pathway in Smooth Muscle Cell MigrationJournal of Biological Chemistry, 1999
- Identification of MAPKAPK Homolog (MAPKAPK-4) as a Myosin II Regulatory Light-Chain Kinase in Sea Urchin Egg ExtractsArchives of Biochemistry and Biophysics, 1997
- Constitutive Activation of Mitogen-activated Protein Kinase-activated Protein Kinase 2 by Mutation of Phosphorylation Sites and an A-helix MotifJournal of Biological Chemistry, 1995
- The Drosophila melanogaster homolog of the mammalian MAPK-activated protein kinase-2 (MAPKAPK-2) lacks a proline-rich N terminusGene, 1995
- Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and ThreonineJournal of Biological Chemistry, 1995
- The Primary Structure of a Human Map Kinase Activated Protein Kinase 2Biochemical and Biophysical Research Communications, 1994
- Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteinsFEBS Letters, 1992