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Molecular and Cellular Biology, November 2003, p. 7732-7741, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7732-7741.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Elimination of Protein Kinase MK5/PRAK Activity by Targeted Homologous Recombination

Yu Shi,1 Alexey Kotlyarov,1 Kathrin Laaß,1 Achim D. Gruber,2 Elke Butt,3 Katrin Marcus,4 Helmut E. Meyer,4 Anke Friedrich,5 Hans-Dieter Volk,5 and Matthias Gaestel1*

Institute of Biochemistry, Medical School Hannover, 30625 Hannover,1 Department of Pathology, School of Veterinary Medicine Hannover, 30559 Hannover,2 Institute of Clinical Biochemistry and Pathobiochemistry, Medical University Clinic, 97080 Würzburg,3 Medical Proteome Center, Ruhr University of Bochum, 44780 Bochum,4 Charite Campus Mitte, Institute of Medical Immunology, Humboldt University, 10098 Berlin, Germany5

Received 12 May 2003/ Returned for modification 30 June 2003/ Accepted 7 July 2003

MK5 (mitogen-activated protein kinase [MAPK]-activated protein kinase 5), also designated PRAK (p38-regulated and -activated kinase), was deleted from mice by homologous recombination. Although no MK5 full-length protein and kinase activity was detected in the MK5 knockout mice, the animals were viable and fertile and did not display abnormalities in tissue morphology or behavior. In addition, these mice did not show increased resistance to endotoxic shock or decreased lipopolysaccharide-induced cytokine production. Hence, MK5 deletion resulted in a phenotype very different from the complex inflammation-impaired phenotype of mice deficient in MK2, although MK2 and MK5 exhibit evolutional, structural, and apparent extensive functional similarities. To explain this discrepancy, we used wild-type cells and embryonic fibroblasts from both MK2 and MK5 knockout mice as controls to reexamine the mechanism of activation, the interaction with endogenous p38 MAPK, and the substrate specificity of both enzymes. In contrast to MK2, which shows interaction with and chaperoning properties for p38 MAPK and which is activated by extracellular stresses such as arsenite or sorbitol treatment, endogenous MK5 did not show these properties. Furthermore, endogenous MK5 is not able to phosphorylate Hsp27 in vitro and in vivo. We conclude that the differences between the phenotypes of MK5- and MK2-deficient mice result from clearly different functional properties of both enzymes.

* Corresponding author. Mailing address: MHH, Institute of Biochemistry, Carl-Neuberg-Str. 1, D-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, November 2003, p. 7732-7741, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7732-7741.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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