Receptor tyrosine kinases (RTKs) form part of the mitogen response pathway involved in the signaling events that control both cell proliferation and differentiation. Mutations in RTKs or their intracellular signal transducer proteins are among the chief causes of oncogenic cell growth. Analysis of the potent actions of these mutant oncoproteins is essential to understanding the mechanics of oncogenesis. The experiments described in this proposal are focused on determining the role of ion channels as targets and physiological mediators of this signaling. We have shown in fibroblasts, that the expression of the oncogenic protein Ras, induces a small conductance, Ca2+ activated K+ channel (SK). Induction of SK channel expression via the activation of growth factor receptor tyrosine kinases known to activate normal Ras, correlates with regulation of cell proliferation. Such a role for K+ channels in mitogenesis could be shown to be an effective target for therapeutic drugs intended to inhibit or stimulate cell proliferation. Thus, the overall goal of this proposal is aimed to specifically analyze mitogenic signaling events in relation to the ion channel activities which they evoke.
