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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA119075-05S1
Application #
8224392
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Ault, Grace S
Project Start
2006-08-30
Project End
2012-07-31
Budget Start
2010-08-26
Budget End
2012-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$133,447
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Tao, X; Hill, K S; Gaziova, I et al. (2014) Silencing Met receptor tyrosine kinase signaling decreased oral tumor growth and increased survival of nude mice. Oral Oncol 50:104-12
Hill, Kristen S; Gaziova, Ivana; Harrigal, Lindsay et al. (2012) Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer. PLoS One 7:e40420
Sastry, Sarita K; Elferink, Lisa A (2011) Checks and balances: interplay of RTKs and PTPs in cancer progression. Biochem Pharmacol 82:435-40
Elferink, Lisa A; Resto, Vicente A (2011) Receptor-tyrosine-kinase-targeted therapies for head and neck cancer. J Signal Transduct 2011:982879
Ying, Haoqiang; Zheng, Hongwu; Scott, Kenneth et al. (2010) Mig-6 controls EGFR trafficking and suppresses gliomagenesis. Proc Natl Acad Sci U S A 107:6912-7
Hill, Kristen S; Lorinczi, Marta; Elferink, Lisa A (2010) Altered down regulation of the receptor tyrosine kinase met in pancreatic adenocarcinoma cells. J Exp Ther Oncol 8:297-312
Gao, Xiu; Lorinczi, Marta; Hill, Kristen S et al. (2009) Met receptor tyrosine kinase degradation is altered in response to the leucine-rich repeat of the Listeria invasion protein internalin B. J Biol Chem 284:774-83
Sheth, Payal R; Hays, John L; Elferink, Lisa A et al. (2008) Biochemical basis for the functional switch that regulates hepatocyte growth factor receptor tyrosine kinase activation. Biochemistry 47:4028-38
Li, Ning; Hill, Kristen S; Elferink, Lisa A (2008) Analysis of receptor tyrosine kinase internalization using flow cytometry. Methods Mol Biol 457:305-17
Li, Ning; Lorinczi, Marta; Ireton, Keith et al. (2007) Specific Grb2-mediated interactions regulate clathrin-dependent endocytosis of the cMet-tyrosine kinase. J Biol Chem 282:16764-75