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Molecular and Cellular Biology, January 2007, p. 170-181, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.01456-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinases MK2 and MK3 Cooperate in Stimulation of Tumor Necrosis Factor Biosynthesis and Stabilization of p38 MAPK{triangledown}

N. Ronkina,1 A. Kotlyarov,1 O. Dittrich-Breiholz,2 M. Kracht,2 E. Hitti,1 K. Milarski,3 R. Askew,3 S. Marusic,4 L.-L. Lin,4 M. Gaestel,1* and J.-B. Telliez4

Institute of Biochemistry,1 Institute of Pharmacology, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany,2 Biological Technology,3 Inflammation Department, Wyeth Research, 200 Cambridge Park Drive, Cambridge, Massachusetts 021404

Received 7 August 2006/ Returned for modification 15 September 2006/ Accepted 2 October 2006

MK2 and MK3 represent protein kinases downstream of p38 mitogen-activated protein kinase (MAPK). Deletion of the MK2 gene in mice resulted in an impaired inflammatory response although MK3, which displays extensive structural similarities and identical functional properties in vitro, is still present. Here, we analyze tumor necrosis factor (TNF) production and expression of p38 MAPK and tristetraprolin (TTP) in MK3-deficient mice and demonstrate that there are no significant differences with wild-type animals. We show that in vivo MK2 and MK3 are expressed and activated in parallel. However, the level of activity of MK2 is always significantly higher than that of MK3. Accordingly, we hypothesized that MK3 could have significant effects only in an MK2-free background and generated MK2/MK3 double-knockout mice. Unexpectedly, these mice are viable and show no obvious defects due to loss of compensation between MK2 and MK3. However, there is a further reduction of TNF production and expression of p38 and TTP in double-knockout mice compared to MK2-deficient mice. This finding, together with the observation that ectopically expressed MK3 can rescue MK2 deficiency similarly to MK2, indicates that both kinases share the same physiological function in vivo but are expressed to different levels.

* 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.

{triangledown} Published ahead of print on 9 October 2006.

Molecular and Cellular Biology, January 2007, p. 170-181, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.01456-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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