Focal adhesion kinase as a regulator of cell tension in the progression of cancer.

Growing evidence indicates that critical steps in cancer progression such as cell adhesion, migration, and cell cycle progression are regulated by the composition and organization of the microenvironment. The adhesion of cancer cells to components of the microenvironment and the forces transmitted to the cells via the actinomyosin network and the signaling complexes organized within focal adhesions allow cancer cells to sense the local topography of the extracellular matrix and respond efficiently to proximal growth and migration promoting cues. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is over expressed in a variety of cancers and plays an important role in cell adhesion, migration, and anchorage-dependent growth. In this review, we summarize evidence which implicate FAK in the ability of cells to sense and respond to local forces from the microenvironment through the regulation of adhesion dynamics and actinomyosin contractility, and we discuss the potential roles of FAK as a mechanosensor in the progression of cancer.

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

[2]  J. Parsons,et al.  Characterization of Graf, the GTPase-activating Protein for Rho Associated with Focal Adhesion Kinase , 1998, The Journal of Biological Chemistry.

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

[4]  E. Kohn,et al.  Regulation of the RhoA pathway in human endothelial cell spreading on type IV collagen: role of calcium influx. , 1999, Journal of cell science.

[5]  Alexander A Spector,et al.  Emergent patterns of growth controlled by multicellular form and mechanics. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[6]  R. Assoian,et al.  Regulation of growth factor signaling and cell cycle progression by cell adhesion and adhesion-dependent changes in cellular tension. , 2005, Cytokine & growth factor reviews.

[7]  Micah Dembo,et al.  Focal adhesion kinase is involved in mechanosensing during fibroblast migration , 2001, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[10]  E. Manser,et al.  PAK and other Rho-associated kinases--effectors with surprisingly diverse mechanisms of regulation. , 2005, The Biochemical journal.

[11]  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.

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

[13]  M. Sheetz,et al.  Cell migration: regulation of force on extracellular-matrix-integrin complexes. , 1998, Trends in cell biology.

[14]  C. Turner,et al.  Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. , 1988, Annual review of cell biology.

[15]  S. Gunst,et al.  Depletion of focal adhesion kinase by antisense depresses contractile activation of smooth muscle. , 2001, American journal of physiology. Cell physiology.

[16]  M. Ishida,et al.  Agonist-stimulated cytoskeletal reorganization and signal transduction at focal adhesions in vascular smooth muscle cells require c-Src. , 1999, The Journal of clinical investigation.

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

[18]  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.

[19]  L. Reichardt,et al.  Control of axonal branching and synapse formation by focal adhesion kinase , 2004, Nature Neuroscience.

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

[21]  J. Taylor,et al.  Cytoskeletal changes induced by GRAF, the GTPase regulator associated with focal adhesion kinase, are mediated by Rho. , 1999, Journal of cell science.

[22]  Christopher S. Chen,et al.  Microfabricated silicone elastomeric post arrays for measuring traction forces of adherent cells. , 2007, Methods in cell biology.

[23]  Kenneth M. Yamada,et al.  Direct transmembrane clustering and cytoplasmic dimerization of focal adhesion kinase initiates its tyrosine phosphorylation. , 2002, Biochimica et biophysica acta.

[24]  L. Addadi,et al.  Force and focal adhesion assembly: a close relationship studied using elastic micropatterned substrates , 2001, Nature Cell Biology.

[25]  Y. Wang,et al.  Cell locomotion and focal adhesions are regulated by substrate flexibility. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Guan,et al.  Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Donna J. Webb,et al.  FAK–Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly , 2004, Nature Cell Biology.

[28]  J. Parsons,et al.  Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src , 1994, Molecular and cellular biology.

[29]  J. Koretz,et al.  Effects of phosphorylation of light chain residues threonine 18 and serine 19 on the properties and conformation of smooth muscle myosin. , 1988, The Journal of biological chemistry.

[30]  S. Hanks,et al.  Roles played by a subset of integrin signaling molecules in cadherin-based cell–cell adhesion , 2004, The Journal of cell biology.

[31]  Yu-Li Wang,et al.  Substrate rigidity regulates the formation and maintenance of tissues. , 2006, Biophysical journal.

[32]  S. Lo,et al.  Focal adhesions: what's new inside. , 2006, Developmental biology.

[33]  D. Schlaepfer,et al.  The Cytoskeletal/Non-muscle Isoform of α-Actinin Is Phosphorylated on Its Actin-binding Domain by the Focal Adhesion Kinase* , 2001, The Journal of Biological Chemistry.

[34]  S. Penman,et al.  Progressive loss of shape-responsive metabolic controls in cells with increasingly transformed phenotype , 1981, Cell.

[35]  J. M. Broome,et al.  The Role of Focal Adhesion Kinase Binding in the Regulation of Tyrosine Phosphorylation of Paxillin* , 1999, The Journal of Biological Chemistry.

[36]  J. Parsons,et al.  p130Cas, a Substrate Associated with v-Src and v-Crk, Localizes to Focal Adhesions and Binds to Focal Adhesion Kinase* , 1996, The Journal of Biological Chemistry.

[37]  N. E. Kemp ELECTRON MICROSCOPY OF GROWING OOCYTES OF RANA PIPIENS , 1956, The Journal of biophysical and biochemical cytology.

[38]  Michael P. Sheetz,et al.  Force transduction by Triton cytoskeletons , 2002, The Journal of cell biology.

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

[40]  Krister Wennerberg,et al.  Rho and Rac Take Center Stage , 2004, Cell.

[41]  B. Kasemo,et al.  A novel cell force sensor for quantification of traction during cell spreading and contact guidance. , 2007, Biophysical journal.

[42]  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.

[43]  C. Shoenberg An Electron Microscope Study of Smooth Muscle in Pregnant Uterus of the Rabbit , 1958, The Journal of Biophysical and Biochemical Cytology.

[44]  Michael P. Sheetz,et al.  Force Sensing by Mechanical Extension of the Src Family Kinase Substrate p130Cas , 2006, Cell.

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

[46]  Radhika Desai,et al.  ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix , 2003, The Journal of cell biology.

[47]  J. Parsons,et al.  Focal adhesion kinase is required for the spatial organization of the leading edge in migrating cells , 2005, Journal of Cell Science.

[48]  Kenneth M. Yamada,et al.  The matrix reorganized: extracellular matrix remodeling and integrin signaling. , 2006, Current opinion in cell biology.

[49]  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.

[50]  J. Gutkind,et al.  Regulation of G Protein-linked Guanine Nucleotide Exchange Factors for Rho, PDZ-RhoGEF, and LARG by Tyrosine Phosphorylation , 2002, The Journal of Biological Chemistry.

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

[52]  W. Arthur,et al.  Integrin engagement suppresses RhoA activity via a c-Src-dependent mechanism , 2000, Current Biology.

[53]  J. Guan,et al.  Phosphorylation of Tyrosine 397 in Focal Adhesion Kinase Is Required for Binding Phosphatidylinositol 3-Kinase* , 1996, The Journal of Biological Chemistry.

[54]  M. Rothkegel,et al.  The molecular architecture of focal adhesions. , 1995, Annual review of cell and developmental biology.

[55]  P. Hawkins,et al.  Phosphoinositide 3‐kinase‐dependent activation of Rac , 2003, FEBS letters.

[56]  Suzanne F. Jones,et al.  Phase 1 study of a focal adhesion kinase (FAK) inhibitor PF-00562271 in patients (pts) with advanced solid tumors , 2007 .

[57]  Matthew J. Paszek,et al.  The Tension Mounts: Mechanics Meets Morphogenesis and Malignancy , 2004, Journal of Mammary Gland Biology and Neoplasia.

[58]  A. Samarel,et al.  Suppression of RhoA Activity by Focal Adhesion Kinase-induced Activation of p190RhoGAP , 2006, Journal of Biological Chemistry.

[59]  S. Gunst,et al.  Selected contribution: roles of focal adhesion kinase and paxillin in the mechanosensitive regulation of myosin phosphorylation in smooth muscle. , 2001, Journal of applied physiology.

[60]  M. Naujokas,et al.  Homologous recombination between transfected DNAs , 1983, Molecular and cellular biology.

[61]  J. Folkman,et al.  Role of cell shape in growth control , 1978, Nature.

[62]  K. Burridge,et al.  Focal adhesions, contractility, and signaling. , 1996, Annual review of cell and developmental biology.

[63]  K. Holzapfel,et al.  Role of focal adhesion kinase (FAK) in renal ischaemia and reperfusion , 2007, Pflügers Archiv - European Journal of Physiology.

[64]  J. Scholey,et al.  Regulation of non-muscle myosin assembly by calmodulin-dependent light chain kinase , 1980, Nature.

[65]  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.

[66]  M. Beuvin,et al.  Activation of Rac1 by Paxillin-Crk-DOCK180 Signaling Complex Is Antagonized by Rap1 in Migrating NBT-II Cells* , 2004, Journal of Biological Chemistry.

[67]  Á. Valverde,et al.  Bombesin stimulation of p125 focal adhesion kinase tyrosine phosphorylation. Role of protein kinase C, Ca2+ mobilization, and the actin cytoskeleton. , 1993, The Journal of biological chemistry.

[68]  Brian P Helmke,et al.  Mechanisms of mechanotransduction. , 2006, Developmental cell.

[69]  H. Pasolli,et al.  Focal adhesion kinase modulates tension signaling to control actin and focal adhesion dynamics , 2007, The Journal of cell biology.

[70]  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.

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

[72]  Benjamin Geiger,et al.  Focal Contacts as Mechanosensors Externally Applied Local Mechanical Force Induces Growth of Focal Contacts by an Mdia1-Dependent and Rock-Independent Mechanism , 2001 .

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

[74]  Ning Wang,et al.  Directional control of lamellipodia extension by constraining cell shape and orienting cell tractional forces , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[75]  S. Hanks,et al.  Mechanisms of CAS Substrate Domain Tyrosine Phosphorylation by FAK and Src , 2001, Molecular and Cellular Biology.

[76]  J. M. Broome,et al.  Paxillin binding is not the sole determinant of focal adhesion localization or dominant-negative activity of focal adhesion kinase/focal adhesion kinase-related nonkinase. , 2000, Molecular biology of the cell.

[77]  Cynthia A. Reinhart-King,et al.  Tensional homeostasis and the malignant phenotype. , 2005, Cancer cell.

[78]  K. Beningo,et al.  Nascent Focal Adhesions Are Responsible for the Generation of Strong Propulsive Forces in Migrating Fibroblasts , 2001, The Journal of cell biology.

[79]  Takayuki Kato,et al.  Cooperation between mDia1 and ROCK in Rho-induced actin reorganization , 1999, Nature Cell Biology.

[80]  F. Matsumura Regulation of myosin II during cytokinesis in higher eukaryotes. , 2005, Trends in cell biology.

[81]  J. Parsons,et al.  PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation , 2003, The Journal of cell biology.

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

[83]  Anne J. Ridley,et al.  The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors , 1992, Cell.

[84]  Y. Wang,et al.  High resolution detection of mechanical forces exerted by locomoting fibroblasts on the substrate. , 1999, Molecular biology of the cell.

[85]  F. Grinnell,et al.  Decreased level of PDGF-stimulated receptor autophosphorylation by fibroblasts in mechanically relaxed collagen matrices , 1993, The Journal of cell biology.

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

[87]  Josef Korinek,et al.  Proceedings of the American Society of Clinical Oncology , 1982 .

[88]  Daniel Choquet,et al.  Extracellular Matrix Rigidity Causes Strengthening of Integrin–Cytoskeleton Linkages , 1997, Cell.

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

[90]  T. Seufferlein,et al.  Lysophosphatidic acid stimulates tyrosine phosphorylation of focal adhesion kinase, paxillin, and p130. Signaling pathways and cross-talk with platelet-derived growth factor. , 1994, The Journal of biological chemistry.

[91]  G. Whitesides,et al.  Cell shape provides global control of focal adhesion assembly. , 2003, Biochemical and biophysical research communications.