SIGNALING MECHANISMS AND REGULATION OF THE PDGF ALPHA RECEPTOR

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The three isoforms of platelet-derived growth factor (PDGF), the two PDGF receptors, and the biochemical processes that the PDGF system regulate is important to our understanding of growth control and numerous medical problems. Because the PDGF alpha-receptor was only recently described and cloned less information is available concerning this component of the PDGF system. The overall goal of this proposed research is to elucidate the function of the alpha-receptor. Our Specific Aims are designed to determine the cellular mechanisms regulating the expression of the PDGF alpha-receptor. We will investigate the control of the normal level of alpha-receptors and the type of synthesis control that regulates the PDGF alpha-receptor immediately after it has been down-regulated by ligand binding. This application seeks to study and compare the alpha and beta PDGF receptor stimulated processes at specific cell cycle times. We will determine the cell processes that the alpha and beta PDGF receptor controls at specific cell cycle times. In addition we will determine the dependency of the PDGF alpha-receptor on Ca++ as compared to the limited dependency of the beta-receptor on Ca++ concentrations. We will determine the mechanism whereby the process stimulated by the beta-receptor are different from those stimulated by the alpha-receptor in their requirement for external Ca++. Our last Specific Aim seeks to determine the difference in growth stimulation by PDGF-AA versus PDGF-BB. Our preliminary data clearly shows that PDGF-BB stimulates competence formation and the PDGF-BB exposure to cells only requires 4 hrs. However, stimulation of cell proliferation by PDGF-AA requires the PDGF-AA to be present continuously. Our understanding of the differences and similarities of the alpha and beta PDGF receptor are important because it is apparent that the isoform of PDGF and the receptor type is used as a regulatory mechanism during growth and development and possibly for other cell types. It is necessary to understand the function of the alpha-receptor in order to clearly understand the function of PDGF in growth control. Experiments to complete these Specific Aims will require the development of antibody and the use of molecular biology to produce specific vectors and to clone the genes required for the competence state induced by PDGF-BB but not induced by PDGF-AA.