By linking extracellular matrix (ECM) proteins to the actin cytoskeleton, integrin proteins regulate cell proliferation, migration, and survival. A key player in integrin signaling is focal adhesion kinase (FAK). Activation and localization of FAK to focal adhesions results from the binding of integrins to ECM proteins. Activated FAK relays signal from integrins to downstream components of different pathways. However, inappropriate activation of FAK and inappropriate FAK-regulated signaling has been implicated in cancer and other human diseases. Therefore, the long-term objective is to investigate structures and molecular mechanisms underlying regulatory and targeting interactions of FAK-regulated signaling pathways. This objective will be achieved through the use of biophysical methods. Studies showed that FAK's C-terminal focal adhesion targeting (FAT) domain is necessary and sufficient for the targeting of FAK to focal adhesions, a crucial step in FAK signaling. On the basis of preliminary findings described in this application, it is hypothesized that the FAT domain regulates FAK activation by interacting with FAK's N-terminal FERM domain. Previously, the principal investigator determined the solution structure of the FAT domain by NMR spectroscopy. In proposed studies, this method will be used to determine the chemical nature of interactions between the FAT domain and its binding partners: paxillin, talin, and FAK's FERM domain. Furthermore, the complex molecular interplay among FAK, paxillin, and talin will be evaluated. These studies will provide structural and functional information at the atomic level about the FAT domain and its associated proteins. Also, ligands designed to serve as FAT domain inhibitors, will be tested to determine whether they provide a lead in developing therapies that interfere specifically with abnormal FAK-mediated signaling that contributes to cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM069916-01
Application #
6712729
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Flicker, Paula F
Project Start
2004-02-01
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
1
Fiscal Year
2004
Total Cost
$270,000
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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