Focal adhesion kinase as potential target for cancer therapy (Review).

Focal adhesion kinase (FAK) is a 125-kDa non-receptor and non-membrane protein tyrosine. FAK can function with integrins and growth factor receptors to promote cell survival dependent kinase activity and nuclear FAK promotes cell proliferation and survival through FERM (FAK, ezrin, radixin, moesin) domain-enhanced p53 degradation independent kinase activity. Many previous studies have indicated that FAK plays a critical role in the biological processes of normal and cancer cells and FAK has been proposed as a potential target in cancer therapy. Small molecule inhibitors (PF-573,228; PF-562,271 and NVP-226) for use as potential cancer therapies have been developed. However, the detailed mechanism of the role for FAK in tumor cell generation and progression remain unclear, so future work is needed to explore these issues. New inhibitors that can be effectively inhibit the function of FAK still need to be explored due to the low specificity, and resistance.

[1]  R. Anderegg,et al.  Activation of a Novel Calcium-dependent Protein-tyrosine Kinase , 1996, The Journal of Biological Chemistry.

[2]  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.

[3]  Jie J. Zheng,et al.  Structural Insight into the Mechanisms of Targeting and Signaling of Focal Adhesion Kinas , 2002, Molecular and Cellular Biology.

[4]  W. Cance,et al.  Attenuation of the expression of the focal adhesion kinase induces apoptosis in tumor cells. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[5]  J. Parsons,et al.  Autonomous expression of a noncatalytic domain of the focal adhesion-associated protein tyrosine kinase pp125FAK , 1993, Molecular and cellular biology.

[6]  D. Kerr,et al.  The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[8]  D. Schlaepfer,et al.  Control of motile and invasive cell phenotypes by focal adhesion kinase. , 2004, Biochimica et biophysica acta.

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

[10]  Michael D Schaller,et al.  The interplay between Src and integrins in normal and tumor biology , 2004, Oncogene.

[11]  C. Livasy,et al.  Upregulation of focal adhesion kinase (FAK) expression in ductal carcinoma in situ (DCIS) is an early event in breast tumorigenesis , 2004, Breast Cancer Research and Treatment.

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

[13]  Bob van de Water,et al.  Focal adhesion kinase: a potential target in cancer therapy. , 2007, Biochemical pharmacology.

[14]  J. Parsons,et al.  Identification of integrin-stimulated sites of serine phosphorylation in FRNK, the separately expressed C-terminal domain of focal adhesion kinase: a potential role for protein kinase A. , 1997, The Biochemical journal.

[15]  C. Damsky,et al.  Extracellular Matrix Survival Signals Transduced by Focal Adhesion Kinase Suppress p53-mediated Apoptosis , 1998, The Journal of cell biology.

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

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

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

[19]  G. Rosen,et al.  Cleavage of Focal Adhesion Kinase by Caspases during Apoptosis* , 1997, The Journal of Biological Chemistry.

[20]  T. Hunter,et al.  Signal transduction from the extracellular matrix--a role for the focal adhesion protein-tyrosine kinase FAK. , 1996, Cell structure and function.

[21]  Nils Cordes,et al.  Signalling via integrins: implications for cell survival and anticancer strategies. , 2007, Biochimica et biophysica acta.

[22]  Gareth E. Jones,et al.  Focal adhesion kinase controls actin assembly via a FERM-mediated interaction with the Arp2/3 complex , 2007, Nature Cell Biology.

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

[24]  C. Damsky,et al.  Matrix survival signaling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. , 2000 .

[25]  M. Schwartz,et al.  Integrins regulate the apoptotic response to DNA damage through modulation of p53 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Frame,et al.  Targeted proteolysis of the focal adhesion kinase pp125 FAK during c-MYC-induced apoptosis is suppressed by integrin signalling. , 1996, Oncogene.

[27]  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.

[28]  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.

[29]  J. Parsons,et al.  A mechanism for regulation of the adhesion-associated protein tyrosine kinase pp125FAK , 1996, Nature.

[30]  Hai Lu,et al.  Squamous cell carcinoma cell aggregates escape suspension-induced, p53-mediated anoikis: fibronectin and integrin alphav mediate survival signals through focal adhesion kinase. , 2004, The Journal of biological chemistry.

[31]  J. Guan,et al.  Transcriptional activation of cyclin D1 promoter by FAK contributes to cell cycle progression. , 2001, Molecular biology of the cell.

[32]  V. Golubovskaya,et al.  TAE226‐Induced apoptosis in breast cancer cells with overexpressed Src or EGFR , 2008, Molecular carcinogenesis.

[33]  J. Parsons,et al.  Inhibition of cell spreading by expression of the C-terminal domain of focal adhesion kinase (FAK) is rescued by coexpression of Src or catalytically inactive FAK: a role for paxillin tyrosine phosphorylation , 1997, Molecular and cellular biology.

[34]  K. Vuori,et al.  The adaptor protein Crk connects multiple cellular stimuli to the JNK signaling pathway. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[35]  V. Golubovskaya,et al.  p53 regulates FAK expression in human tumor cells , 2008, Molecular carcinogenesis.

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

[37]  W. Yung,et al.  Inhibition of both focal adhesion kinase and insulin-like growth factor-I receptor kinase suppresses glioma proliferation in vitro and in vivo , 2007, Molecular Cancer Therapeutics.

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

[39]  Martin E M Noble,et al.  The structural basis of localization and signaling by the focal adhesion targeting domain. , 2002, Structure.

[40]  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.

[41]  R. Assoian,et al.  Growth control by intracellular tension and extracellular stiffness. , 2008, Trends in cell biology.

[42]  M. Eck,et al.  Crystal Structure of the FERM Domain of Focal Adhesion Kinase* , 2006, Journal of Biological Chemistry.

[43]  R. Liddington,et al.  The focal adhesion targeting (FAT) region of focal adhesion kinase is a four-helix bundle that binds paxillin , 2002, Nature Structural Biology.

[44]  J. Parsons,et al.  Regulated Expression of Focal Adhesion Kinase-Related Nonkinase, the Autonomously Expressed C-Terminal Domain of Focal Adhesion Kinase , 1999, Molecular and Cellular Biology.

[45]  M. Brown,et al.  Identification of LIM3 as the principal determinant of paxillin focal adhesion localization and characterization of a novel motif on paxillin directing vinculin and focal adhesion kinase binding , 1996, The Journal of cell biology.

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

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

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

[49]  G. Draetta.  Mammalian G1 cyclins. , 1994, Current opinion in cell biology.

[50]  C. Beaudry,et al.  Differential role of proline-rich tyrosine kinase 2 and focal adhesion kinase in determining glioblastoma migration and proliferation. , 2003, Molecular cancer research : MCR.

[51]  T. Hunter,et al.  Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases , 1996, Molecular and cellular biology.

[52]  J. Taylor,et al.  A Role for Focal Adhesion Kinase in Phenylephrine-induced Hypertrophy of Rat Ventricular Cardiomyocytes* , 2000, The Journal of Biological Chemistry.

[53]  J. Parsons,et al.  Interaction of Focal Adhesion Kinase with Cytoskeletal Protein Talin (*) , 1995, The Journal of Biological Chemistry.

[54]  E. Ruoslahti,et al.  Control of adhesion-dependent cell survival by focal adhesion kinase , 1996, The Journal of cell biology.

[55]  J. Parsons,et al.  Induction of Apoptosis after Expression of PYK2, a Tyrosine Kinase Structurally Related to Focal Adhesion Kinase , 1997, The Journal of cell biology.

[56]  S. R. Datta,et al.  Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery , 1997, Cell.

[57]  C. Turner,et al.  Tyrosine phosphorylation of paxillin and pp125FAK accompanies cell adhesion to extracellular matrix: a role in cytoskeletal assembly , 1992, The Journal of cell biology.

[58]  D. Brenner,et al.  The Focal Adhesion Kinase Suppresses Transformation-associated, Anchorage-independent Apoptosis in Human Breast Cancer Cells , 2000, The Journal of Biological Chemistry.

[59]  E. Peles,et al.  Protein tyrosine kinase PYK2 involved in Ca2+-induced regulation of ion channel and MAP kinase functions , 1995, Nature.

[60]  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.

[61]  C. Livasy,et al.  Focal Adhesion Kinase Overexpression in Endometrial Neoplasia , 2004, Applied immunohistochemistry & molecular morphology : AIMM.

[62]  W. Cance,et al.  The COOH-terminal domain of the focal adhesion kinase induces loss of adhesion and cell death in human tumor cells. , 1998, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

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

[64]  C. Morimoto,et al.  Direct association of pp125FAK with paxillin, the focal adhesion- targeting mechanism of pp125FAK , 1995, The Journal of experimental medicine.

[65]  J. Parsons,et al.  Identification of sequences required for the efficient localization of the focal adhesion kinase, pp125FAK, to cellular focal adhesions , 1993, The Journal of cell biology.

[66]  Zhiqiang Li,et al.  Antisense oligonucleodes targeting the focal adhesion kinase inhibit proliferation, induce apoptosis and cooperate with cytotoxic drugs in human glioma cells , 2006, Journal of Neuro-Oncology.

[67]  Shiro Watanabe,et al.  FAK Is the Upstream Signal Protein of the Phosphatidylinositol 3-Kinase-Akt Survival Pathway in Hydrogen Peroxide-induced Apoptosis of a Human Glioblastoma Cell Line* , 1999, The Journal of Biological Chemistry.

[68]  C. Gladson,et al.  New concepts regarding focal adhesion kinase promotion of cell migration and proliferation , 2006, Journal of cellular biochemistry.

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

[70]  C. Livasy,et al.  Overexpression of focal adhesion kinase in primary colorectal carcinomas and colorectal liver metastases: immunohistochemistry and real-time PCR analyses. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[71]  V. Golubovskaya,et al.  Direct Interaction of the N-terminal Domain of Focal Adhesion Kinase with the N-terminal Transactivation Domain of p53* , 2005, Journal of Biological Chemistry.

[72]  V. Golubovskaya,et al.  Focal adhesion kinase and cancer. , 2009, Histology and histopathology.

[73]  D. Schlaepfer,et al.  Inhibition of focal adhesion kinase expression or activity disrupts epidermal growth factor-stimulated signaling promoting the migration of invasive human carcinoma cells. , 2001, Cancer research.

[74]  Q. Ding,et al.  Focal adhesion kinase is expressed in the angiogenic blood vessels of malignant astrocytic tumors in vivo and promotes capillary tube formation of brain microvascular endothelial cells. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[75]  S. Grant,et al.  Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. , 2004, Genes & development.

[76]  Jie J. Zheng,et al.  Structural features of the focal adhesion kinase–paxillin complex give insight into the dynamics of focal adhesion assembly , 2005, Protein science : a publication of the Protein Society.

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

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

[79]  Robert A. H. White,et al.  Identification and Characterization of a Novel Related Adhesion Focal Tyrosine Kinase (RAFTK) from Megakaryocytes and Brain (*) , 1995, The Journal of Biological Chemistry.

[80]  Guillermina Lozano,et al.  MDM2, an introduction. , 2003, Molecular cancer research : MCR.

[81]  Christopher A Lipinski,et al.  The tyrosine kinase pyk2 promotes migration and invasion of glioma cells. , 2005, Neoplasia.

[82]  Terukatsu Sasaki,et al.  Cloning and Characterization of Cell Adhesion Kinase β, a Novel Protein-tyrosine Kinase of the Focal Adhesion Kinase Subfamily (*) , 1995, The Journal of Biological Chemistry.

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

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

[85]  D. Yamamoto,et al.  FAK overexpression upregulates cyclin D3 and enhances cell proliferation via the PKC and PI3-kinase-Akt pathways. , 2003, Cellular signalling.

[86]  S. Kanner,et al.  A transmembrane-anchored chimeric focal adhesion kinase is constitutively activated and phosphorylated at tyrosine residues identical to pp125FAK. , 1994, The Journal of biological chemistry.

[87]  Kenneth M. Yamada,et al.  Taking Cell-Matrix Adhesions to the Third Dimension , 2001, Science.

[88]  G. Semenza,et al.  Molecular Events Implicated in Brain Tumor Angiogenesis and Invasion , 2000, Pediatric Neurosurgery.

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

[90]  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.

[91]  J. Parsons,et al.  Regulation of focal adhesion targeting and inhibitory functions of the FAK related protein FRNK using a novel estrogen receptor "switch". , 2002, Cell motility and the cytoskeleton.

[92]  D. Beer,et al.  Dual Tyrosine Kinase Inhibitor for Focal Adhesion Kinase and Insulin-like Growth Factor-I Receptor Exhibits Anticancer Effect in Esophageal Adenocarcinoma In vitro and In vivo , 2008, Clinical Cancer Research.

[93]  K. Nave,et al.  FAK Deficiency in Cells Contributing to the Basal Lamina Results in Cortical Abnormalities Resembling Congenital Muscular Dystrophies , 2003, Neuron.

[94]  S. Hanks,et al.  Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases , 1995, Molecular and cellular biology.

[95]  J. Parsons,et al.  Selective Expression of an Endogenous Inhibitor of FAK Regulates Proliferation and Migration of Vascular Smooth Muscle Cells , 2001, Molecular and Cellular Biology.

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

[97]  K. Vousden.  Switching from life to death: the Miz-ing link between Myc and p53. , 2002, Cancer cell.

[98]  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.

[99]  I. Zachary,et al.  Focal adhesion kinase. , 1997, The international journal of biochemistry & cell biology.

[100]  S. Hanks,et al.  Anti-apoptotic Role of Focal Adhesion Kinase (FAK) , 2000, The Journal of Biological Chemistry.

[101]  R L Juliano,et al.  Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine kinase. , 1992, The Journal of biological chemistry.

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