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Molecular and Cellular Biology, July 2002, p. 4827-4835, Vol. 22, No. 13
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.13.4827-4835.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Distinct Cellular Functions of MK2

Alexey Kotlyarov,1 Yvonne Yannoni,2 Susann Fritz,1 Kathrin Laaß,1 Jean-Baptiste Telliez,2 Deborah Pitman,2 Lih-Ling Lin,2 and Matthias Gaestel1*

Institute of Biochemistry, Medical School Hannover, Hannover 30625, Germany,1 Musculoskeletal Science, Genetics Institute, Wyeth Research, Cambridge, Massachusetts 021402

Received 26 November 2001/ Returned for modification 23 January 2002/ Accepted 26 March 2002

Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) is activated upon stress by p38 MAPK{alpha} and -ß, 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.

* Corresponding author. Mailing address: Medical School Hannover, Inst. of Biochemistry, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Phone: 49 511 532 2825. Fax: 49 511 532 2827. E-mail: Gaestel.Matthias{at}mh-hannover.de.

Molecular and Cellular Biology, July 2002, p. 4827-4835, Vol. 22, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.13.4827-4835.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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