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Originally published In Press as doi:10.1074/jbc.M407669200 on July 28, 2004

J. Biol. Chem., Vol. 279, Issue 43, 44731-44739, October 22, 2004
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MAP Kinase Phosphatase 3 (MKP3) Interacts with and Is Phosphorylated by Protein Kinase CK2{alpha}*

Marco Castelli{ddagger}, Montserrat Camps{ddagger}, Corine Gillieron{ddagger}, Didier Leroy{ddagger}, Steve Arkinstall§, Christian Rommel{ddagger}, and Anthony Nichols{ddagger}||

From the {ddagger}Serono Pharmaceutical Research Institute, Serono International S.A., Plan-les-Ouates 1228, Geneva CH1228, Switzerland and §Serono Reproductive Biology Institute, Inc., Randolph, Massachusetts 02368

Mitogen-activated protein (MAP) kinases play a central role in controlling a wide range of cellular functions following their activation by a variety of extracellular stimuli. MAP kinase phosphatases (MKPs) represent a subfamily of dual specificity phosphatases, which negatively regulate MAP kinases. Although ERK2 activity is regulated by its phosphorylation state, MKP3 is regulated by physical interaction with ERK2, independent of its enzymatic activity (Camps, M., Nichols, A., Gillieron, C., Antonsson, B., Muda, M., Chabert, C., Boschert, U., and Arkinstall, S., (1998) Science 280, 1262–1265; Farooq, A., Chaturvedi, G., Mujtaba, S., Plotnikova, O., Zeng, L., Dhalluin, C., Ashton, R., and Zhou, M. M. (2001), Mol. Cell 7, 387–399; Zhou, B., and Zhang, Z. Y. (1999) J. Biol. Chem. 274, 35526–35534). The interaction of ERK2 and MKP3 allows the reciprocal cross-regulation of their catalytic activity. Indeed, MKP3 acts as a negative regulator on ERK2-MAP kinase signal transduction activity, representing thus a negative feedback for this MAPK pathway. To identify novel proteins able to complex MKP3, we used the yeast two-hybrid system. Here we report that MKP3 and protein kinase CK2 form a protein complex, which can include ERK2. The phosphatase activity of MKP3 is then slightly increased in vitro, whereas in transfected cells, ERK2 dephosphorylation is reduced. In addition, we demonstrated that CK2 selectively phosphorylates MKP3, suggesting cross-regulation between CK2{alpha} and MKP3, as well as a modulation of ERK2-MAPK signaling by CK2{alpha} via MKP3.


Received for publication, July 8, 2004

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed. Tel.: 41-22-706-96-66; Fax: 41-22-794-69-65; E-mail: christian.rommel{at}serono.com. || To whom correspondence may be addressed. Tel.: 41-22-706-96-66; Fax: 41-22-794-69-65; E-mail: anthony.nichols{at}serono.com.


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