The overall objective of this study is to determine whether activating mutations near the Met tyrosine kinase domain are tumorigenic due to altered substrate specificity and the activation of distinct signaling pathways. The somatic and germline Met mutations present in papillary renal carcinomas have been examined by the Vande Woude lab and others in several in vitro systems, however, the mechanisms by which activated Met induces neoplastic transformation are poorly understood. To further study the effects of mutated Met in vivo, the Vande Woude lab has generated mice with targeted mutations (knock-in or ki) in the Met locus, representative of both somatic and germline activating mutations present in papillary renal carcinomas. The activated Met molecules have varying tumorigenic activities in the knock-in mice. The variable tumor profiles of ki-mice will be used to dissect the Met-mediated signaling pathways that are critical to tumor development.
Specific aims of this study are (1) to determine if different activating mutations in Met will produce distinct phenotypes in a knock-in mouse model, (2) to determine if HGF/SF is required for tumor development in the presence of mutationally activated Met, and (3) to investigate the hypothesis that specific signaling pathways are activated by mutated Met and mediate tumorigenesis in the met knock-in mice. These studies may not only identify the genetic events and signaling molecules crucial to Met-mediated tumorigenesis but may also improve our overall understanding of receptor tyrosine kinase signaling in cancer progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA105748-03
Application #
7121236
Study Section
Special Emphasis Panel (ZRG1-F09 (20))
Program Officer
Jakowlew, Sonia B
Project Start
2004-09-01
Project End
2007-08-30
Budget Start
2006-10-31
Budget End
2007-08-30
Support Year
3
Fiscal Year
2007
Total Cost
$44,540
Indirect Cost
Name
Van Andel Research Institute
Department
Type
DUNS #
129273160
City
Grand Rapids
State
MI
Country
United States
Zip Code
49503
Graveel, Carrie R; DeGroot, Jack D; Su, Yanli et al. (2009) Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer. Proc Natl Acad Sci U S A 106:12909-14