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Department of Pharmacology
Judy L. Meinkoth, Ph.D.

Education:

1985

Ph.D. (Biology)

University of California, San Diego

Research Summary:
My laboratory studies crosstalk between cAMP, Ras and Rap1 in the control of cell proliferation, differentiation and survival using microinjection and other molecular and cell biological approaches. Although many effects of cAMP are mediated through protein kinase A (PKA), the effects of cAMP are far more diverse. We have shown that in cells where cAMP stimulates proliferation, it does so through divergent pathways, only some of which require PKA. Other cAMP-mediated signals lead to the activation of Rap1 and Ras through unknown mechanisms. Not only does cAMP activate multiple pathways, it also influences other signaling pathways. In cells where PKA and Ras together stimulate proliferation, they do so through signaling pathways that do not include Raf-1 and the MAPK cascade. In this case, cAMP acts as a switch to divert signals from Ras to alternate effector pathways including phosphatidylinositol 3-kinase (PI3K) and an exchange factor for the Ras-related protein Ral (RalGDS). Crosstalk between cAMP, Ras and Rap1 is not limited to the control of cell proliferation. In thyroid cells, Ras reverses cAMP-mediated differentiation through unknown effectors while Rap1A promotes cell differentiation. Acute expression of activated Ras in thyroid cells stimulates apoptosis. In contrast, thyroid cells selected to stably express oncogenic Ras exhibit hormone-independent cell proliferation and morphologic transformation. The secondary events that transpire to allow cell survival in the face of activated Ras are critically important as Ras mutations occur at high frequency in thyroid cancer. Crosstalk between Ras and Rap1-mediated signaling in neoplastic transformation is under investigation. PKC activity is increased in thyroid tumors, where mutations in PKCe have been identified. The roles of individual PKC isozymes in the regulation of thyroid cell proliferation and survival, and their potential roles in Ras-mediated signaling, is another area of ongoing interest.