EFFECT OF RAF FAMILY PROTEIN KINASES ON CELL PHYSIOLOGY

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Since the identification of v-raf as the oncogene of the acutely transforming retrovirus, 3611-murine sarcoma virus, significant progress has been made in the molecular and functional characterization of raf proteins and their effects on cell physiology. (1) Amino terminally truncated versions of c-raf-1 and A-raf-1 are transforming in vitro and in vivo. (2) raf proteins are cytoplasmically located protein kinases related to the src gene superfamily and truncated versions possess ser/thr-specific protein kinase activity. Moreover, c-raf and A-raf show homology to protein kinase C, not only in the C-terminal kinase domain, but also in the N-terminal putative regulatory domain. (3) raf- transformed fibroblasts release transforming growth factor(s) (TGF), express TGF- alpha mRNA in certain cases, and are inhibited in collagen synthesis. (4) Functional assays utilizing NIH 3T3 cells that are growth arrested by microinjection of ras monoclonal antibody or transformation of flat revertants of Kirsten sarcoma virus-transformed fibroblasts suggest that raf family oncogenes act independent of ras, either through a signal transduction pathway not involving ras or one in which raf has a positive downstream of ras.