KINASE ENCODING PROTO-ONCOGENES IN IL-2 SIGNAL TRANSDUCT

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The lymphokine interleukin-2 (IL2) is a critical regulator of lymphocyte growth and immune responses, and is beginning to find clinical uses for the treatment of cancer and immune disorders. Greater knowledge of the molecular mechanisms of IL2signal transduction, therefore, could ultimately contribute to improved pharmacological manipulation of in vivo immune responses or modulation of lymphoma and leukemic cell growth. Despite cloning of IL2 and its receptor genes and extensive investigations using a variety of approaches, little is known about the mechanisms of IL2-signal transduction. Unlike many other growth factor receptors, the IL2-binding molecules on lymphocytes lack tyrosine-kinase activity, and yet both tyrosine and serine/ threonine phosphorylation of intracellular proteins are rapid events in IL2-stimulated T-cells. Clearly, therefore, IL2 and its receptor must regulate the activity of kinases in lymphocytes. Recently, we have found that IL2 induces tyrosine phosphorylation and elevated activity of the RAF-1 kinase, a serine-threonine-specific kinase with homology to the transforming gene of MSV-3611 retrovirus. This kinase has been implicated previously in the regulation of mitogenesis and malignant transformation in several types of cells, including lymphocytes. We will explore the mechanisms responsible for phosphorylation and activation of the RAF-1 kinase in IL2-stimulated T-cells. Further we will investigate the effects of this kinase on the regulation of T-cell growth. These studies will contribute to an improved understanding of the intracellular mechanisms of IL2 action, and may provide insights into the growth factor/oncogene networks involved in the development and progression of leukemias and lymphomas.