RAPLB AS AN EFFECTOR OF CAMP MEDIATED MITOGENIC ACTION

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Extensive evidence implicates cAMP as a modulator of cell proliferation in mammalian cells and suggests that cAMP could be a potential target for new therapeutic avenues. However, the specific effector/s that mediate the effects of cAMP remain elusive. The identification of these effectors would allow targeting this specific branch for the development of improved drugs. Rap1 is a member of the Ras superfamily of G-proteins originally isolated as a Ras-revertant clone. The strong structural and biochemical similarities with the Ras oncogene in combination with new observations indicate that Rap1 proteins might also exert positive effects on the control of cell growth, and collaborate in the process of malignant transformation. First, cAMP-elevating agents convert Rap1b into its active GTPbound conformation, providing biochemical evidence that Rap1 is a downstream effector for cAMP. Second, elevated expression of Rap1b in model systems where cAMP is mitogenic causes enhanced proliferation with signs of malignant transformation. Finally, tuberous sclerosis (a human genetic syndrome characterized by the development of tumors in a variety of tissues) was recently associated with the loss of tuberin, a protein that showed Rap1-GAP activity, potentially leading to constitutive activation of Rap1 in those tumors. Altogether, these observations have prompted our studies to define Rap1b as an effector of cAMP actions on cell growth, and to determine if its deregulated function is associated with malignant transformation. The specific aims of this proposal are (I) To determine if Rap1b's mitogenic effects are downstream of cAMP, 2) To assess the involvement of Rap1b phosphorylation on its mitogenic activity, 3) To characterize RGL2 as a potential effector for Raplb/cAMP mitogenic action, and 4) To determine if Rap1b is able to deregulate cell growth in cAMP responsive cell lines. The long term goal of this research will be to characterize the newly identified Rap1b function as a positive effector of cell proliferation, emphasizing its role as an effector of the cAMP- mediated mitogenic response.