The importance of Hepatocyte Growth Factor Receptor signaling in normal and pathological conditions is well established. Poor regulation of Hepatocyte Growth Factor Receptor signaling underlies several human cancers including invasive breast, gastrointestinal and hepatic carcinomas, correlating closely with metastatic tendency, angiogenesis and poor prognosis. Endocytic studies on many cell surface receptors suggest that receptor signaling and trafficking function cooperatively to determine signaling endpoints in vivo. In this context increased metastasis and angiogenesis are distinguishing features of Hepatocyte Growth Factor Receptor signaling suggesting that the receptor itself is subject to tight regulation by specific signaling cascades and endocytic mechanisms. Activation of Hepatocyte Growth Factor Receptor by ligand binding triggers receptor internalization and eventual down regulation. However it is presently unclear how Hepatocyte Growth Factor Receptor signaling is coupled to this endocytic response and the subsequent cellular phenotypes. In this exploratory R21 proposal we will test the hypothesis that signaling from the Hepatocyte Growth Factor Receptor regulates its own internalization. Our preliminary studies show that the Hepatocyte Growth Factor Receptor is internalized exclusively through clathrin-coated pits and that distinct subsets of downstream signaling adaptors regulate this process. The exploratory studies proposed in this R21 will further define the requirement of distinct receptor-adaptor interactions for receptor internalization (Aim 1) and delineate their mechanism of action, with particular focus on recruitment of receptor into coated pits, vesicle budding and transport via the early endosomes (Aim 2). Achieving these aims will provide the necessary tools and approaches for future studies aimed at delineating the molecular mechanisms coupling Hepatocyte Growth Factor Receptor trafficking with its signaling properties and provide data that may be useful in the development of novel therapeutic strategies. ? ?
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