Regulation of a Kinase Cascade Involved in Cancer and Normal Cell Growth.
Annual rept. 1 Jun 95-31 May 96,
CASE WESTERN RESERVE UNIV CLEVELAND OH
Pagination or Media Count:
Among the signaling pathways regulated by growth promoting receptor kinases, one of the best characterized is the p42p44 MAPK Mitogen-Activated Protein Kinase pathway. In this cytoplasmic kinase cascade, c-Raf SerThi kinase phosphorylates and activates MEKl2 MAPKERK Kinasel - and 2 which in turn activate p42p44 MAPKs by phosphorylation. MEKK MEK Kinase, originally cloned based on sequence homology to yeast kinases BYR2 and STEll, also was able to phosphorylate and activate MEKi in vitro and in vivo overexpression system. However, we found Raf and MEKK show different site preference in phosphorylating MEK, suggesting biochemically these two kinases are not identical. Unlike Raf, MEKK lacks the transformation capacity in cell transformation assay. Instead, expression of activated mutant of MEKK DMEKK displayed cell growth inhibition activity. In vivo, MEKK modulates a separate kinase cascade in which MEKK phosphorylates and activates SEKi also known as MKK4 or JNKKl which is a direct upstream activating kinase of SAPKJNK Stress-Activated-Protein-Kinasec-Jun N-terminal Kinase. In addition, MEKK fails to activate p38, another subfamily of MAPKs involved in stress response, and may even play a role in downmodulating the p38 pathway.
- Medicine and Medical Research