Mip1, an MEKK2-interacting protein, controls MEKK2 dimerization and activation.
Mitogen-activated protein kinase ( MAPK) cascades are central components of the intracellular signaling networks used by eukaryotic cells to respond to a wide spectrum of extracellular stimuli. An MAPK is activated by an MAPK kinase, which in turn is activated by an MAPK kinase kinase ( MAP3K). However, little is known about the molecular aspects of the regulation and activation of large numbers of MAP3Ks that are crucial in relaying upstream receptor-mediated signals through the MAPK cascades to induce various physiological responses. In this study, we identified a novel MEKK2-interacting protein, Mip1, that regulates MEKK2 dimerization and activation by forming a complex with inactive and nonphosphorylated MEKK2. In particular, Mip1 prevented MEKK2 activation by blocking MEKK2 dimer formation, which in turn blocked JNKK2, c-Jun N-terminal kinase 1 ( JNK1), extracellular signal-regulated kinase 5, and AP-1 reporter gene activation by MEKK2. Furthermore, we found that the endogenous Mip1- MEKK2 complex was dissociated transiently following epidermal growth factor stimulation. In contrast, the knockdown of Mip1 expression by siRNA augmented the MEKK2- mediated JNK and AP-1 reporter activation. Together, our data suggest a novel model for MEKK2 regulation and activation.[1]References
- Mip1, an MEKK2-interacting protein, controls MEKK2 dimerization and activation. Cheng, J., Zhang, D., Kim, K., Zhao, Y., Zhao, Y., Su, B. Mol. Cell. Biol. (2005) [Pubmed]
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