Cell surface interactions influence many intercommunicating signalling pathways that ultimately affect cell proliferation and differentiated functions. One of the best studied examples of signalling pathway crosstalk involves cAMP and Ras-mediated pathways. The present dogma is that cAMP inhibits proliferation in most cell types by uncoupling Ras from its downstream effectors such as Raf1 and other members of a cytoplasmic and nuclear kinase cascade. Very much underrepresented in the literature are cells, such as thyroid cells, in which cAMP stimulates, rather than inhibits, cell proliferation. Paradoxically, TSH requires Ras for its mitogenic effect despite the fact that the hormone increases cellular cAMP levels. In thyroid cells, Ras signals through unknown pathways that do not involve Raf1 and the MAP kinase cascade. Therefore, the principal investigator plans to elucidate the molecular components of TSH mitogenic pathways, including the identification of new Ras effectors active in thyroid cells as well as the interaction between Ras and cAMP signalling pathways. These goals will be accomplished by microinjection into individual thyroid cells of purified signalling molecules and a variety of their inhibitors. These studies will lead to a better understanding of the mechanism by which TSH stimulates thyroid cell growth.
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