Signals from both integrin and growth factor receptors combine to promote and coordinate events such as cell motility. Work from a number of labs has identified the focal adhesion kinase (FAK) as a component of both integrin and growth factor receptor signaling pathways. However, the biological function of FAK is not well defined as it has been proposed to mediate cell survival, cell cycle progression, and cell motility signaling events. Studies from our laboratory using FAK-null and FAK-reconstituted cells have demonstrated that interactions mediated by the FAK N-terminal (NT) or C-terminal (CT) domain play a critical and differential roles in facilitating either growth factor or integrin-stimulated cell migration, respectively. This proposal aims are focused on determining the specific molecular connections of how FAK functions as a receptor-proximal regulator of cell migration. First, we will identify the binding site for the beta1-integrin-associated protein talin in the FAK-CT domain to elucidate how FAK is connected to and activated by beta1-integrins. Second, we will determine the direct binding site of the FAK-NT FERM (band 4.1, ezrin, radixin, moesin homology) domain on the activated EGF receptor and which of the three FAK FERM domain lobes functions to mediate EGFr association important for FAK transphosphorylation. Third, we will evaluate the effects of tetracycline regulatable expression of FAK and mutants thereof in FAK-null cells. These studies are focused on identifying: the functional sites on FAK required to promote either focal contact remodeling and Rho GTPase inactivation, sites required for the enhancement of EGF and fibronectin-stimulated ERK/MAP and JNK/SAP kinase activation, and the determination as to whether these are the same sites required to promote growth factor and integrin-stimulated cell motility. Finally, we will use normal, FAK-null, and FAK-reconstituted fibroblasts to characterize the role of FAK in modulating EGF and fibronectin-stimulated early response gene expression events. These gain-of-function experiments seek to establish a model system in which to delineate the structure-function workings of FAK in promoting signaling leading to enhanced cell migration.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087038-02
Application #
6514625
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Ault, Grace S
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
2
Fiscal Year
2002
Total Cost
$345,861
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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MasiƠ-BalaguƩ, Miriam; Izquierdo, Ismael; Garrido, Georgina et al. (2015) Gastrin-stimulated G?13 Activation of Rgnef Protein (ArhGEF28) in DLD-1 Colon Carcinoma Cells. J Biol Chem 290:15197-209
Young, Shanique A; McCabe, Katelyn E; Bartakova, Alena et al. (2015) Integrin ?4 Enhances Metastasis and May Be Associated with Poor Prognosis in MYCN-low Neuroblastoma. PLoS One 10:e0120815
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Lim, Ssang-Taek; Chen, Xiao Lei; Lim, Yangmi et al. (2008) Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell 29:9-22
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Lim, Yangmi; Lim, Ssang-Taek; Tomar, Alok et al. (2008) PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility. J Cell Biol 180:187-203
Ilic, Dusko; Mao-Qiang, Man; Crumrine, Debra et al. (2007) Focal adhesion kinase controls pH-dependent epidermal barrier homeostasis by regulating actin-directed Na+/H+ exchanger 1 plasma membrane localization. Am J Pathol 170:2055-67
Schlaepfer, David D; Hou, Shihe; Lim, Ssang-Taek et al. (2007) Tumor necrosis factor-alpha stimulates focal adhesion kinase activity required for mitogen-activated kinase-associated interleukin 6 expression. J Biol Chem 282:17450-9
Mitra, Satyajit K; Schlaepfer, David D (2006) Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18:516-23

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