Growth factors induce a variety of cellular responses including proliferation, survival and migration. A number of growth factors activate receptors with intrinsic tyrosine kinase activity. Extensive studies in cell culture systems have shown that receptor engagement leads to binding of intracellular effectors, and the activation of individual signaling pathways. However, the physiological relevance of utilizing one or another pathway remains mostly unknown. In this proposal, we will focus on identifying the roles of individual signaling pathways downstream of platelet derived growth factors (PDGFs), which are involved in developmental and physiological responses in many tissues, including the vasculature, the kidney, the skeleton and neural crest derivatives. We will achieve our goals by generating mutant mice that express PDGF receptors in which the individual docking sites for various effectors have been mutated. We will further concentrate our efforts on determining if signaling pathways between PDGF receptors and other growth factor receptors are redundant, using genetic substitution methods. To further investigate the role of PDGF signaling in development, we will make use of conditional gene ablation to test the role of PDGF signaling in specific tissues. These studies should help us understand growth factor regulatory mechanisms, and provide information on the specificity and interplay of growth factor signaling pathways in physiological processes.
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