The Hepatocyte Growth Factor Receptor (cMet) is a receptor tyrosine kinase critical for normal cellular responses, such as cell growth, survival and motility. Normally, cMet signaling is tightly regulated. However, increased cMet signaling occurs in many cancers, including pancreatic carcinomas, correlating closely with early-stage invasion, dissemination and metastasis. Our long-term goal is to identify (and eventually regulate) the molecular mechanisms that promote inactivation of cMet signaling in metastatic pancreatic cancers. Endocytosis is the key pathway for terminating cMet signaling, by targeting the receptor for lysosomal degradation. This project will define the molecular mechanisms that normally regulate cMet internalization and deactivation, and determine whether the endocvtic trafficking of this critical receptor is disrupted in metastatic pancreatic tumors. Our preliminary data show that following activation, cMet is internalized exclusively through clathrin-coated pits. Moreover, cMet internalization and degradation are regulated by distinct subsets of signaling molecules downstream of cMet activation. Our preliminary data also show that cMet degradation is impaired in a metastatic pancreatic adenocarcinoma. We hypothesize that in addition to their established roles in regulating cMet signaling, these signaling molecules link activated cMet to the clathrin-dependent endocvtic machinery for internalization, and that dysregulated cMet internalization and/or degradation could contribute to persistent cMet signaling in certain pancreatic metastases. Our project will test these hypotheses by defining the cMet internalization step(s) regulated by these signaling molecules (Aim 1); delineate the signaling mechanisms downstream of receptor activation that are essential for cMet internalization (Aim 2); and determine which components of the endocytic machinery are modified in response to cMet activation (Aim 3). Finally, we will examine if a common lesion or multiple defects in cMet endocytic trafficking contribute to increased receptor levels and signaling in metastatic pancreatic tumor cells (Aim 4). ? ? Pancreatic cancer is a devastating disease, with a 5-year survival rate below 5% due to its high metastatic tendency, difficult early detection, and resistance to conventional treatments. Novel therapeutic strategies are thus urgently needed. Our approach would be to inactivate cMet signaling in tumor cells by inducing receptor endocytosis and inactivation. Our project is novel in that it should elucidate the molecular mechanisms involved in deactivating cMet signaling and how they are dysregulated in pancreatic cancers, an essential prerequisite for designing therapeutic agents targeting pancreatic cancers in which sustained cMet signaling facilitates metastasis. ? ? ?
