Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis.

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays critical roles in integrin-mediated signal transductions and also participates in signaling by other cell surface receptors. In integrin-mediated cell adhesion, FAK is activated via disruption of an auto-inhibitory intra-molecular interaction between its amino terminal FERM domain and the central kinase domain. The activated FAK forms a complex with Src family kinases, which initiates multiple downstream signaling pathways through phosphorylation of other proteins to regulate different cellular functions. Multiple downstream signaling pathways are identified to mediate FAK regulation of migration of various normal and cancer cells. Extensive studies in cultured cells as well as conditional FAK knockout mouse models indicated a critical role of FAK in angiogenesis during embryonic development and cancer progression. More recent studies also revealed kinase-independent functions for FAK in endothelial cells and fibroblasts. Consistent with its roles in cell migration and angiogenesis, increased expression and/or activation of FAK are found in a variety of human cancers. Therefore, small molecular inhibitors for FAK kinase activity as well as future development of novel therapies targeting the potentially kinase-independent functions of FAK are promising treatments for metastatic cancer as well as other diseases.

[1]  E. Gherardi,et al.  Regulation of cell movement: the motogenic cytokines. , 1991, Biochimica et biophysica acta.

[2]  S. Hanks,et al.  Focal adhesion protein-tyrosine kinase phosphorylated in response to cell attachment to fibronectin. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[3]  V. Golubovskaya,et al.  Focal adhesion kinase and p53 signaling in cancer cells. , 2007, International review of cytology.

[4]  Jihe Zhao,et al.  Signal transduction by focal adhesion kinase in cancer , 2009, Cancer and Metastasis Reviews.

[5]  M. Schaller.  Biochemical signals and biological responses elicited by the focal adhesion kinase. , 2001, Biochimica et biophysica acta.

[6]  D. Schlaepfer,et al.  Direct Interaction of Focal Adhesion Kinase with p190RhoGEF* , 2003, Journal of Biological Chemistry.

[7]  J. Parsons,et al.  Mislocalization or Reduced Expression of Arf GTPase-activating Protein ASAP1 Inhibits Cell Spreading and Migration by Influencing Arf1 GTPase Cycling* , 2005, Journal of Biological Chemistry.

[8]  J. Parsons,et al.  pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Susan J Fisher,et al.  Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. , 2008, Molecular cell.

[10]  D. Schlaepfer,et al.  Required role of focal adhesion kinase (FAK) for integrin-stimulated cell migration. , 1999, Journal of cell science.

[11]  M. Schaller,et al.  FAK regulates biological processes important for the pathogenesis of cancer , 2003, Cancer and Metastasis Reviews.

[12]  V. Golubovskaya,et al.  Dual Inhibition of Focal Adhesion Kinase and Epidermal Growth Factor Receptor Pathways Cooperatively Induces Death Receptor-mediated Apoptosis in Human Breast Cancer Cells* , 2002, The Journal of Biological Chemistry.

[13]  R. Flavell,et al.  Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis , 2005, The Journal of cell biology.

[14]  C. Turner,et al.  JCB Article , 2001 .

[15]  J. Guan,et al.  Role of Grb7 Targeting to Focal Contacts and Its Phosphorylation by Focal Adhesion Kinase in Regulation of Cell Migration* , 2000, The Journal of Biological Chemistry.

[16]  D. Shalloway,et al.  Regulation of focal adhesion-associated protein tyrosine kinase by both cellular adhesion and oncogenic transformation , 1992, Nature.

[17]  J. Girault,et al.  Autophosphorylation-independent and -dependent Functions of Focal Adhesion Kinase during Development* , 2009, The Journal of Biological Chemistry.

[18]  J. Guan,et al.  FAK-mediated src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation. , 2005, Developmental cell.

[19]  J. Guan,et al.  Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. , 1996, Journal of cell science.

[20]  R L Juliano,et al.  Signal transduction by integrins: increased protein tyrosine phosphorylation caused by clustering of beta 1 integrins. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[21]  L. Romer,et al.  Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation. , 1996, Molecular biology of the cell.

[22]  J. Guan,et al.  Regulation of Focal Adhesion Kinase by Its Amino-Terminal Domain through an Autoinhibitory Interaction , 2003, Molecular and Cellular Biology.

[23]  Ann Y Park,et al.  Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development , 2010, The Journal of cell biology.

[24]  J. Taylor,et al.  An SH3 domain-containing GTPase-activating protein for Rho and Cdc42 associates with focal adhesion kinase , 1996, Molecular and cellular biology.

[25]  S. Lim,et al.  Knock-in Mutation Reveals an Essential Role for Focal Adhesion Kinase Activity in Blood Vessel Morphogenesis and Cell Motility-Polarity but Not Cell Proliferation* , 2010, The Journal of Biological Chemistry.

[26]  R. Braren,et al.  Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation , 2006, The Journal of cell biology.

[27]  G. Borisy,et al.  Cell Migration: Integrating Signals from Front to Back , 2003, Science.

[28]  F. Fiedorek,et al.  Mapping of the focal adhesion kinase (Fadk) gene to mouse Chromosome 15 and human Chromosome 8 , 1995, Mammalian Genome.

[29]  S. Hanks,et al.  Focal adhesion kinase is abundant in developing blood vessels and elevation of its phosphotyrosine content in vascular smooth muscle cells is a rapid response to angiotensin II , 1994, Journal of cellular biochemistry.

[30]  D. Cheresh,et al.  Requirement of vascular integrin alpha v beta 3 for angiogenesis. , 1994, Science.

[31]  J. Parsons,et al.  Focal adhesion kinase: the first ten years , 2003, Journal of Cell Science.

[32]  R. Klemke,et al.  Regulation of Cell Contraction and Membrane Ruffling by Distinct Signals in Migratory Cells , 1999, The Journal of cell biology.

[33]  M. Gardel,et al.  PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility , 2008, The Journal of cell biology.

[34]  S. Hanks,et al.  Cloning of a Xenopus laevis cDNA encoding focal adhesion kinase (FAK) and expression during early development. , 1995, Gene.

[35]  J. Parsons,et al.  Monoclonal antibodies to individual tyrosine-phosphorylated protein substrates of oncogene-encoded tyrosine kinases. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Guan,et al.  Association of Grb7 with Phosphoinositides and Its Role in the Regulation of Cell Migration* , 2002, The Journal of Biological Chemistry.

[37]  D. Schlaepfer,et al.  Integrin-regulated FAK-Src signaling in normal and cancer cells. , 2006, Current opinion in cell biology.

[38]  J. Guan,et al.  Residues within the First Subdomain of the FERM-like Domain in Focal Adhesion Kinase Are Important in Its Regulation* , 2005, Journal of Biological Chemistry.

[39]  Matthew D. Wessel,et al.  Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. , 2008, Cancer research.

[40]  R. Hynes,et al.  An MBoC Favorite: Fibronectin/integrin interaction induces tyrosine phosphorylation of a 120-kDa protein , 1991, Molecular biology of the cell.

[41]  C. Erickson.  Cell migration in the embryo and adult organism. , 1990, Current opinion in cell biology.

[42]  S. Hanks,et al.  Potential role for focal adhesion kinase in migrating and proliferating keratinocytes near epidermal wounds and in culture. , 1994, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[43]  J. Guan,et al.  Association of Focal Adhesion Kinase with Grb7 and Its Role in Cell Migration* , 1999, The Journal of Biological Chemistry.

[44]  S. C. Liu,et al.  The FERM domain: A unique module involved in the linkage of cytoplasmic proteins to the membrane , 1998 .

[45]  D. Schlaepfer,et al.  The Focal Adhesion Kinase‐‐A Regulator of Cell Migration and Invasion , 2002, IUBMB life.

[46]  H. Kung,et al.  Regulation of the PH-domain-containing tyrosine kinase Etk by focal adhesion kinase through the FERM domain , 2001, Nature Cell Biology.

[47]  S. Aizawa,et al.  Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice , 1995, Nature.

[48]  Liz Y. Han,et al.  Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. , 2007, Cancer research.

[49]  D. A. Hanson,et al.  Focal adhesion kinase: in command and control of cell motility , 2005, Nature Reviews Molecular Cell Biology.

[50]  Richard O Hynes,et al.  Integrins Bidirectional, Allosteric Signaling Machines , 2002, Cell.

[51]  D. Lauffenburger,et al.  Cell Migration: A Physically Integrated Molecular Process , 1996, Cell.

[52]  M. Schwartz,et al.  Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover. , 2000, Journal of cell science.

[53]  G. Koh,et al.  Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion. , 2000, Circulation research.

[54]  J. Girault,et al.  The N-termini of FAK and JAKs contain divergent band 4.1 domains. , 1999, Trends in biochemical sciences.

[55]  S. Hanks,et al.  Identification of p130Cas as a Mediator of Focal Adhesion Kinase–promoted Cell Migration , 1998, The Journal of cell biology.

[56]  J. Parsons,et al.  Focal Adhesion Kinase: Targeting Adhesion Signaling Pathways for Therapeutic Intervention , 2008, Clinical Cancer Research.

[57]  J. Guan,et al.  Requirement of Phosphatidylinositol 3-Kinase in Focal Adhesion Kinase-promoted Cell Migration* , 1999, The Journal of Biological Chemistry.

[58]  A. Bresnick,et al.  Roles of Rho-associated Kinase and Myosin Light Chain Kinase in Morphological and Migratory Defects of Focal Adhesion Kinase-null Cells* , 2002, The Journal of Biological Chemistry.

[59]  H. Ueda,et al.  Overexpression of focal adhesion kinase in vascular endothelial cells promotes angiogenesis in transgenic mice. , 2004, Cardiovascular research.

[60]  C. Damsky,et al.  FAK integrates growth-factor and integrin signals to promote cell migration , 2000, Nature Cell Biology.

[61]  S. Hanks,et al.  Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130Cas. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[62]  J. Guan,et al.  Mechanisms of focal adhesion kinase regulation. , 2005, Current cancer drug targets.

[63]  S. Lim,et al.  FERM control of FAK function: Implications for cancer therapy , 2008, Cell cycle.

[64]  K. Vuori,et al.  CAS/Crk Coupling Serves as a “Molecular Switch” for Induction of Cell Migration , 1998, The Journal of cell biology.

[65]  Xinming Cai,et al.  Structural Basis for the Autoinhibition of Focal Adhesion Kinase , 2007, Cell.

[66]  A. Karginov,et al.  The association of ASAP1, an ADP ribosylation factor-GTPase activating protein, with focal adhesion kinase contributes to the process of focal adhesion assembly. , 2002, Molecular biology of the cell.

[67]  T. Takenawa,et al.  Focal Adhesion Kinase Regulation of N-WASP Subcellular Localization and Function* , 2004, Journal of Biological Chemistry.

[68]  C. Turner,et al.  Paxillin LD4 Motif Binds PAK and PIX through a Novel 95-kD Ankyrin Repeat, ARF–GAP Protein: A Role in Cytoskeletal Remodeling , 1999, The Journal of cell biology.

[69]  D. Schlaepfer,et al.  Multiple connections link FAK to cell motility and invasion. , 2004, Current opinion in genetics & development.

[70]  S. Hanks,et al.  Induced Focal Adhesion Kinase (FAK) Expression in FAK-Null Cells Enhances Cell Spreading and Migration Requiring Both Auto- and Activation Loop Phosphorylation Sites and Inhibits Adhesion-Dependent Tyrosine Phosphorylation of Pyk2 , 1999, Molecular and Cellular Biology.

[71]  Christopher Autry,et al.  Cellular Characterization of a Novel Focal Adhesion Kinase Inhibitor* , 2007, Journal of Biological Chemistry.

[72]  D. Sheppard,et al.  Src-mediated coupling of focal adhesion kinase to integrin αvβ5 in vascular endothelial growth factor signaling , 2002, The Journal of cell biology.

[73]  J. Girault,et al.  Ezrin Interacts with Focal Adhesion Kinase and Induces Its Activation Independently of Cell-matrix Adhesion* , 2001, The Journal of Biological Chemistry.

[74]  F. Sarkar,et al.  Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin. , 1995, The Journal of clinical investigation.

[75]  M. Eck,et al.  FERM Domain Interaction Promotes FAK Signaling , 2004, Molecular and Cellular Biology.

[76]  J. Parsons,et al.  Focal adhesion kinase and paxillin bind to peptides mimicking beta integrin cytoplasmic domains , 1995, The Journal of cell biology.

[77]  C. Turner,et al.  Tyrosine kinase activity, cytoskeletal organization, and motility in human vascular endothelial cells. , 1994, Molecular biology of the cell.

[78]  Osamu Ohmori,et al.  A novel low‐molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth , 2007, Molecular carcinogenesis.

[79]  M. Becker‐André,et al.  Expression of an N-terminally truncated form of human focal adhesion kinase in brain. , 1993, Biochemical and biophysical research communications.

[80]  L. Liotta,et al.  Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. , 1974, Cancer research.

[81]  I. Macdonald,et al.  Metastasis: Dissemination and growth of cancer cells in metastatic sites , 2002, Nature Reviews Cancer.

[82]  D. A. Hanson,et al.  Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors , 2006, Oncogene.

[83]  Neil O. Carragher,et al.  The role of focal-adhesion kinase in cancer — a new therapeutic opportunity , 2005, Nature Reviews Cancer.

[84]  S. Hanks,et al.  The Signaling and Biological Implications of FAK Overexpression in Cancer , 2006, Clinical Cancer Research.

[85]  W. Cance,et al.  Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumors. , 1995, Cancer research.

[86]  D. Cheresh,et al.  The role of alphav integrins during angiogenesis: insights into potential mechanisms of action and clinical development. , 1999, The Journal of clinical investigation.

[87]  L. Claesson‐Welsh,et al.  VEGF-induced activation of phosphoinositide 3-kinase is dependent on focal adhesion kinase. , 2001, Experimental cell research.

[88]  G. Nemerow,et al.  Differential regulation of cell motility and invasion by FAK , 2003, The Journal of cell biology.

[89]  R. Klemke,et al.  Extracellular-Regulated Kinase Activation and Cas/Crk Coupling Regulate Cell Migration and Suppress Apoptosis during Invasion of the Extracellular Matrix , 2000, The Journal of cell biology.

[90]  W. Cance,et al.  Expression of focal adhesion kinase gene and invasive cancer , 1993, The Lancet.

[91]  S. Hanks,et al.  Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility. , 2003, Frontiers in bioscience : a journal and virtual library.

[92]  S. Mizutani,et al.  Both focal adhesion kinase and c-Ras are required for the enhanced matrix metalloproteinase 9 secretion by fibronectin in ovarian cancer cells. , 1998, Cancer research.