MAP kinase phosphatase 3 (MKP3) interacts with and is phosphorylated by protein kinase CK2alpha.
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 CK2alpha and MKP3, as well as a modulation of ERK2-MAPK signaling by CK2alpha via MKP3.
Serono Pharmaceutical Research Institute, Serono International S.A., Plan-les-Ouates 1228, Geneva CH1228, Switzerland.
Marco
M
Castelli
Montserrat
M
Camps
Corine
C
Gillieron
Didier
D
Leroy
Steve
S
Arkinstall
Christian
C
Rommel
Anthony
A
Nichols
D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D047390:Casein Kinase II / Q000378:metabolism*; D002384:Catalysis; D020134:Catalytic Domain; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054642:Dual Specificity Phosphatase 6; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D047468:Immunoprecipitation; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D020798:Two-Hybrid System Techniques
D018076:DNA, Complementary; D011994:Recombinant Proteins; D006639:Histidine; D004247:DNA; D005982:Glutathione Transferase; D047390:Casein Kinase II; D019950:Mitogen-Activated Protein Kinase 1; D010749:Phosphoprotein Phosphatases; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse; D017027:Protein Tyrosine Phosphatases