Activation by Insulin, Growth Factors, and Pharmacological Agents

Activation by Insulin, Growth Factors, and Pharmacological Agents 

Mitogen-Activated Protein Kinase Cascade Members, Including the Protein Kinases raf, MEKK, andMEK 

MAPK is activated by a unique dual function kinase called MEK, which is an acronym for MAPK and ERK-kinase (Crews et al, 1992 Zheng and Guan, 1993). MEK has also been named MAPK-kinase (or MAPKK) and is unusual because it phosphorylates MAPK on both a threonine and a tyrosine amino acid. MEK consists of a family of at least three protein kinase isoforms, each of which shows differential reactivity toward the different members of the MAPK family. Each MEK isoform is activated through phosphorylation mechanisms. When fully dephosphorylated, MEK is inactive. When phosphorylated by either MEK-kinase (MEKK) or the proto-oncogene raf, the phosphotransferase activity of MEK is turned on. Although both raf and MEKK can activate MEK, differential activation of either of these kinases can lead to the activation of different downstream signal transduction pathways. Therefore, the roles of raf and MEKK in the cell are not limited to MEK and, therefore, MAPK activation. 

The proto-oncogene ra/becomes active in response to ras stimulation. However, the mechanisms through which ras accomplishes this are only partially understood. Ras requires post-translational modification (farnesylation) to effect cellular transformation and the activation of the enzymes, raf and MAPK (Itoh et al, 1993). It appears that ras functions primarily to localize raf to the surface membrane, where additional factors are involved in the subsequent activation of raf 

The sites on proteins covalently phosphorylated by MAPK suggest that this kinase has a very specific substrate phosphorylation consensus sequence. One of the first proteins identified as a substrate for MAPK was myelin basic protein (MBP). Phosphorylation of 

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