REGULATION OF THE MAPK ERK3

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DESCRIPTION: (Applicant's Description) Protein kinases occupy an important position in normal cellular proliferation, differentiation, and cancer. The extracellular signal regulated kinase family (erks) have recently been shown to be critical in the transmission of extracellular signals regulating mitogenesis, differentiation, and the cellular response to environmental stresses such as heat, ultraviolet light, and osmotic stress. Erk-1 and erk-2 principally serve to transduce mitogenic and differentiation signals, while Jun N- terminal kinase (JNK) and the p38 MAPK are involved in mediating the cellular response to stress. Clinically, JNK and the p38 MAPK are emerging as important molecules in the cellular response to septic shock, fever, and radiation. The applicant proposes to study erk-3, a member of the erk family bearing over 50 percent homology to erk-l and erk-2 in the kinase catalytic domain. Recent reports suggest that erk-3 may be targeted in certain types of cancers, including acute non-lymphoblastic leukemias and in colon cancer. It is the goal of this application to dissect the function and regulation of the erk-3 MAPK. The applicant proposes to first identify the physiological conditions that promote erk-3 activation in order to identify an activator of erk-3. She will do this by identifying activating conditions for this kinase in order to purify an active form of the enzyme. The active preparation of enzyme will be used to evaluate whether phosphorylation is required for the activity of this protein. Should this prove to be the case, she will use a combined strategy of biochemistry and molecular biology to attempt to purify the kinase(s) that activate erk-3. If the regulator is novel, she will clone it. If the activity of erk-3 is shown to be independent of its phosphorylation state, she will use a two hybrid screen to identify potential erk-3 regulators. Second, she proposes to identify and characterize regulatory domains within the erk-3 MAPK. Third, she has demonstrated that in vitro, erk-3 phosphorylates the transcription factors c-Jun and ATF-2. She proposes to investigate the effect of that phosphorylation on DNA-binding and transcription in vivo and in vitro.