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Molecular and Cellular Biology, August 2002, p. 5761-5768, Vol. 22, No. 16
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.16.5761-5768.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Disruption of Mekk2 in Mice Reveals an Unexpected Role for MEKK2 in Modulating T-Cell Receptor Signal Transduction

Zijian Guo,^1, Gavin Clydesdale,¹ Jinke Cheng,¹ Kihwan Kim,¹ Lin Gan,² David J. McConkey,³ Stephen E. Ullrich,¹ Yuan Zhuang,^4* and Bing Su^1*

Departments of Immunology,¹ Biochemistry,² Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030,³ Department of Immunology, Duke University, Durham, North Carolina 27710⁴

Received 3 April 2002/ Returned for modification 7 May 2002/ Accepted 21 May 2002

MEKK2 is a member of the mitogen-activated protein kinase (MAPK) kinase kinase gene family involved in regulating multiple MAPK signaling pathways. To elucidate the in vivo function of MEKK2, we generated mice carrying a targeted mutation in the Mekk2 locus. Mekk2^-/- mice are viable and fertile. Major subsets of thymic and spleen T cells in Mekk2-deficient mice were indistinguishable from those in wild-type mice. B-cell development appeared to proceed similarly in the bone marrow of Mekk2-deficient and wild-type mice. However, Mekk2^-/- T-cell proliferation was augmented in response to anti-CD3 monoclonal antibody (MAb) stimulation, and these T cells produced more interleukin 2 and gamma interferon than did the wild-type T cells, suggesting that MEKK2 may be involved in controlling the strength of T-cell receptor (TCR) signaling. Consistently, Mekk2^-/- thymocytes were more susceptible than wild-type thymocytes to anti-CD3 MAb-induced cell death. Furthermore, TCR-mediated c-Jun N-terminal kinase activation was not blocked but moderately enhanced in Mekk2^-/- T cells. Neither extracellular signal-regulated kinase nor p38 MAPK activation was affected in Mekk2^-/- T cells. In conclusion, we found that MEKK2 may be required for controlling the strength of TCR/CD3 signaling.

Present address: Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China.

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