The long term goal of the proposed research is to understand how signal transduction cascades initiated by extracellular matrix-integrin interactions regulate cell adhesion, cell motility, cell growth and differentiation. Our goal is to understand how such signaling pathways are organized (wired) in normal cells and to ultimately define the cellular alterations (both genetic and environmental) that lead to abnormal adhesion signaling in cancer cells. Studies over the past five years have identified two major classes of signaling molecules that participate in and regulate adhesion signaling, protein tyrosine kinases and members of the family of small GTPases. How these two classes of regulatory proteins function to organize the complex signaling required for cell adhesion and movement is a central theme of this proposal. The proposed studies focus specifically on the role of focal adhesion kinase in mediating signals from the extracellular matrix through the beta- integrin receptors. The three aims emphasize the identification and characterization of molecules that directly interact with FAK and link both upstream and downstream signaling components; defining the role of FAK and interacting partners in mediating signals that regulate cell motility and growth; and finally studying how cells utilize a potentially novel mechanism to regulate adhesion signaling during development.
The specific aims are: 1) Using our base of knowledge about the structural organization of the domains of FAK and the related protein tyrosine kinase PYK2, identify new structural and functional linkages by defining new binding/interacting partners for FAK; 2) examine the functional role of FAK in the regulation of cell migration, focusing initially on fibronectin induced motility. We will also explore the role of FAK in the regulation of cell motility using FAK null fibroblasts derived from mice containing a conditional deletion of FAK (Cre-mediate deletion of a FAK exon flanked by lox P sites); 3) explore the possible in vivo regulation of adhesion signaling by the cell/tissue type-specific expression of the C-terminal domain of FAK, FRNK FAK-related Non-Kinase) and examine the consequences of knocking out FRNK on the course and extent of normal development of the mouse.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA080606-01
Application #
2795936
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Program Officer
Mohla, Suresh
Project Start
1999-03-01
Project End
2003-12-31
Budget Start
1999-03-01
Budget End
1999-12-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Parsons, J Thomas; Slack-Davis, Jill; Tilghman, Robert et al. (2008) Focal adhesion kinase: targeting adhesion signaling pathways for therapeutic intervention. Clin Cancer Res 14:627-32
Iwanicki, Marcin P; Vomastek, Tomas; Tilghman, Robert W et al. (2008) FAK, PDZ-RhoGEF and ROCKII cooperate to regulate adhesion movement and trailing-edge retraction in fibroblasts. J Cell Sci 121:895-905
Tilghman, Robert W; Parsons, J Thomas (2008) Focal adhesion kinase as a regulator of cell tension in the progression of cancer. Semin Cancer Biol 18:45-52
Hayasaka, Haruko; Martin, Karen H; Hershey, E Daniel et al. (2007) Disruption of FRNK expression by gene targeting of the intronic promoter within the focal adhesion kinase gene. J Cell Biochem 102:947-54
Hayasaka, Haruko; Simon, Kate; Hershey, E Daniel et al. (2005) FRNK, the autonomously expressed C-terminal region of focal adhesion kinase, is uniquely regulated in vascular smooth muscle: analysis of expression in transgenic mice. J Cell Biochem 95:1248-63
Liu, Yunhao; Yerushalmi, Gil M; Grigera, Pablo R et al. (2005) Mislocalization or reduced expression of Arf GTPase-activating protein ASAP1 inhibits cell spreading and migration by influencing Arf1 GTPase cycling. J Biol Chem 280:8884-92
Tilghman, Robert W; Slack-Davis, Jill K; Sergina, Natalia et al. (2005) Focal adhesion kinase is required for the spatial organization of the leading edge in migrating cells. J Cell Sci 118:2613-23
Slack-Davis, Jill K; Eblen, Scott T; Zecevic, Maja et al. (2003) PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J Cell Biol 162:281-91
Parsons, J Thomas (2003) Focal adhesion kinase: the first ten years. J Cell Sci 116:1409-16
Liu, Yunhao; Loijens, Joost C; Martin, Karen H et al. (2002) The association of ASAP1, an ADP ribosylation factor-GTPase activating protein, with focal adhesion kinase contributes to the process of focal adhesion assembly. Mol Biol Cell 13:2147-56

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