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FAK and Pyk2 in disease

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Frontiers in Biology

Abstract

Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are non-receptor protein tyrosine kinases that are involved in cell proliferation, migration and survival. Current research of FAK and Pyk2 is greatly focused in cancer biology and several small molecule inhibitors are being tested under clinical development. Like cancer, certain chronic diseases such as cardiovascular disease, bone disease, fibrosis, rheumatoid arthritis, and neurological disorders, share malignant characteristics of cancer. Accumulating evidence has demonstrated that FAK and Pyk2 contribute to other proliferative and degenerative diseases. Thus, the goal of this review is to briefly highlight studies that have implicated FAK and Pyk2 as players in disease progression.

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References

  • Avraham H, Park S Y, Schinkmann K, Avraham S (2000). RAFTK/ Pyk2-mediated cellular signalling. Cell Signal, 12(3): 123–133

    Article  CAS  PubMed  Google Scholar 

  • Avraham S, London R, Fu Y, Ota S, Hiregowdara D, Li J, Jiang S, Pasztor L M, White R A, Groopman J E, et al (1995). Identification and characterization of a novel related adhesion focal tyrosine kinase (RAFTK) from megakaryocytes and brain. J Biol Chem, 270(46): 27742–27751

    Article  CAS  PubMed  Google Scholar 

  • Bae Y H, Mui K L, Hsu B Y, Liu S L, Cretu A, Razinia Z, Xu T, Puré E, Assoian R K (2014). A FAK-Cas-Rac-lamellipodin signaling module transduces extracellular matrix stiffness into mechanosensitive cell cycling. Sci Signal, 7(330): ra57

    Article  PubMed  PubMed Central  Google Scholar 

  • Barsukov I L, Prescot A, Bate N, Patel B, Floyd D N, Bhanji N, Bagshaw C R, Letinic K, Di Paolo G, De Camilli P, Roberts G C, Critchley D R (2003). Phosphatidylinositol phosphate kinase type 1gamma and beta1-integrin cytoplasmic domain bind to the same region in the talin FERM domain. J Biol Chem, 278(33): 31202–31209

    Article  CAS  PubMed  Google Scholar 

  • Bayer A L, Heidkamp M C, Patel N, Porter M J, Engman S J, Samarel A M (2002). PYK2 expression and phosphorylation increases in pressure overload-induced left ventricular hypertrophy. Am J Physiol Heart Circ Physiol, 283(2): H695–H706

    Article  CAS  PubMed  Google Scholar 

  • Beggs H E, Schahin-Reed D, Zang K, Goebbels S, Nave K A, Gorski J, Jones K R, Sretavan D, Reichardt L F (2003). FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies. Neuron, 40(3): 501–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buckbinder L, Crawford D T, Qi H, Ke H Z, Olson L M, Long K R, Bonnette P C, Baumann A P, Hambor J E, Grasser WA, Pan L C, Owen T A, Luzzio M J, Hulford C A, Gebhard D F, Paralkar V M, Simmons H A, Kath J C, Roberts WG, Smock S L, Guzman-Perez A, Brown T A, Li M (2007). Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis. Proc Natl Acad Sci USA, 104(25): 10619–10624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cai X, Lietha D, Ceccarelli D F, Karginov A V, Rajfur Z, Jacobson K, Hahn K M, Eck M J, Schaller M D (2008). Spatial and temporal regulation of focal adhesion kinase activity in living cells. Mol Cell Biol, 28(1): 201–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ceccarelli D F, Song H K, Poy F, Schaller M D, Eck MJ (2006). Crystal structure of the FERM domain of focal adhesion kinase. J Biol Chem, 281(1): 252–259

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Kubalak S W, Chien K R (1998). Ventricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis. Development, 125(10): 1943–1949

    CAS  PubMed  Google Scholar 

  • Cheng Z, Di Michele L A, Hakim Z S, Rojas M, Mack C P, Taylor J M (2012). Targeted focal adhesion kinase activation in cardiomyocytes protects the heart from ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol, 32(4): 924–933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clemente C F, Tornatore T F, Theizen T H, Deckmann A C, Pereira T C, Lopes-Cendes I, Souza J R, Franchini K G (2007). Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice. Circ Res, 101(12): 1339–1348

    Article  CAS  PubMed  Google Scholar 

  • Cooper L A, Shen T L, Guan J L (2003). Regulation of focal adhesion kinase by its amino-terminal domain through an autoinhibitory interaction. Mol Cell Biol, 23(22): 8030–8041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di Michele L A, Doherty J T, Rojas M, Beggs H E, Reichardt L F, Mack C P, Taylor J M (2006). Myocyte-restricted focal adhesion kinase deletion attenuates pressure overload-induced hypertrophy. Circ Res, 99(6): 636–645

    Article  Google Scholar 

  • Ding Q, Gladson C L, Wu H, Hayasaka H, Olman M A (2008). Focal adhesion kinase (FAK)-related non-kinase inhibits myofibroblast differentiation through differential MAPK activation in a FAKdependent manner. J Biol Chem, 283(40): 26839–26849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duong L T, Nakamura I, Lakkakorpi P T, Lipfert L, Bett A J, Rodan G A (2001). Inhibition of osteoclast function by adenovirus expressing antisense protein-tyrosine kinase 2. J Biol Chem, 276(10): 7484–7492

    Article  CAS  PubMed  Google Scholar 

  • Fan Y, Abrahamsen G, Mills R, Calderón C C, Tee J Y, Leyton L, Murrell W, Cooper-White J, McGrath J J, Mackay-Sim A (2013). Focal adhesion dynamics are altered in schizophrenia. Biol Psychiatry, 74(6): 418–426

    Article  PubMed  Google Scholar 

  • Gil-Henn H, Destaing O, Sims N A, Aoki K, Alles N, Neff L, Sanjay A, Bruzzaniti A, De Camilli P, Baron R, Schlessinger J (2007). Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2(-/-) mice. J Cell Biol, 178(6): 1053–1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goñi G M, Epifano C, Boskovic J, Camacho-Artacho M, Zhou J, Bronowska A, Martín M T, Eck M J, Kremer L, Gräter F, Gervasio F L, Perez-Moreno M, Lietha D (2014). Phosphatidylinositol 4,5- bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes. Proc Natl Acad Sci USA, 111 (31): E3177–E3186

    Article  PubMed  PubMed Central  Google Scholar 

  • Hakim Z S, Di Michele L A, Rojas M, Meredith D, Mack C P, Taylor JM (2009). FAK regulates cardiomyocyte survival following ischemia/ reperfusion. J Mol Cell Cardiol, 46(2): 241–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itonaga I, Fujikawa Y, Sabokbar A, Murray D W, Athanasou N A (2000). Rheumatoid arthritis synovial macrophage-osteoclast differentiation is osteoprotegerin ligand-dependent. J Pathol, 192(1): 97–104

    Article  CAS  PubMed  Google Scholar 

  • Kharbanda S, Saleem A, Yuan Z, Emoto Y, Prasad K V, Kufe D (1995). Stimulation of human monocytes with macrophage colony-stimulating factor induces a Grb2-mediated association of the focal adhesion kinase pp125FAK and dynamin. Proc Natl Acad Sci USA, 92(13): 6132–6136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein E A, Yin L, Kothapalli D, Castagnino P, Byfield F J, Xu T, Levental I, Hawthorne E, Janmey P A, Assoian R K (2009). Cellcycle control by physiological matrix elasticity and in vivo tissue stiffening. Curr Biol, 19(18): 1511–1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuppuswamy D, Kerr C, Narishige T, Kasi V S, Menick D R, Cooper G 4th (1997). Association of tyrosine-phosphorylated c-Src with the cytoskeleton of hypertrophying myocardium. J Biol Chem, 272(7): 4500–4508

    Article  CAS  PubMed  Google Scholar 

  • Lagares D, Busnadiego O, García-Fernández R A, Kapoor M, Liu S, Carter D E, Abraham D, Shi-Wen X, Carreira P, Fontaine B A, Shea B S, Tager A M, Leask A, Lamas S, Rodríguez-Pascual F (2012). Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation. Arthritis Rheum, 64(5): 1653–1664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lagares D, Kapoor M (2013). Targeting focal adhesion kinase in fibrotic diseases. BioDrugs, 27(1): 15–23

    Article  CAS  PubMed  Google Scholar 

  • Leask A, Abraham D J (2004). TGF-beta signaling and the fibrotic response. FASEB J, 18(7): 816–827

    Article  CAS  PubMed  Google Scholar 

  • Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio J M, Plowman G D, Rudy B, Schlessinger J (1995). Protein tyrosine kinase PYK2 involved in Ca(2 +)-induced regulation of ion channel and MAP kinase functions. Nature, 376(6543): 737–745

    Article  CAS  PubMed  Google Scholar 

  • Lietha D, Cai X, Ceccarelli D F, Li Y, Schaller M D, Eck M J (2007). Structural basis for the autoinhibition of focal adhesion kinase. Cell, 129(6): 1177–1187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim S T, Chen X L, Lim Y, Hanson D A, Vo T T, Howerton K, Larocque N, Fisher S J, Schlaepfer D D, Ilic D (2008). Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell, 29(1): 9–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim S T, Chen X L, Tomar A, Miller N L, Yoo J, Schlaepfer D D (2010a). Knock-in mutation reveals an essential role for focal adhesion kinase activity in blood vessel morphogenesis and cell motility-polarity but not cell proliferation. J Biol Chem, 285(28): 21526–21536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim S T, Miller N L, Chen X L, Tancioni I, Walsh C T, Lawson C, Uryu S, Weis SM, Cheresh D A, Schlaepfer D D (2012). Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression. J Cell Biol, 197(7): 907–919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim S T, Miller N L, Nam J O, Chen X L, Lim Y, Schlaepfer D D (2010b). Pyk2 inhibition of p53 as an adaptive and intrinsic mechanism facilitating cell proliferation and survival. J Biol Chem, 285(3): 1743–1753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lipinski C A, Loftus J C (2010). Targeting Pyk2 for therapeutic intervention. Expert Opin Ther Targets, 14(1): 95–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu S, Xu S W, Kennedy L, Pala D, Chen Y, Eastwood M, Carter D E, Black C M, Abraham D J, Leask A (2007). FAK is required for TGFbeta-induced JNK phosphorylation in fibroblasts: implications for acquisition of a matrix-remodeling phenotype. Mol Biol Cell, 18(6): 2169–2178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsumoto Y, Tanaka K, Hirata G, Hanada M, Matsuda S, Shuto T, Iwamoto Y (2002). Possible involvement of the vascular endothelial growth factor-Flt-1-focal adhesion kinase pathway in chemotaxis and the cell proliferation of osteoclast precursor cells in arthritic joints. J Immunol, 168(11): 5824–5831

    Article  CAS  PubMed  Google Scholar 

  • McCartney-Francis N L, Frazier-Jessen M, Wahl S M (1998). TGF-beta: a balancing act. Int Rev Immunol, 16(5-6): 553–580

    Article  CAS  PubMed  Google Scholar 

  • Mitra S K, Hanson D A, Schlaepfer D D (2005). Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol, 6(1): 56–68

    Article  CAS  PubMed  Google Scholar 

  • Mui K L, Bae Y H, Gao L, Liu S L, Xu T, Radice G L, Chen C S, Assoian R K (2015). N-Cadherin Induction by ECM Stiffness and FAK Overrides the Spreading Requirement for Proliferation of Vascular Smooth Muscle Cells. Cell Rep, Ossovskaya, V., Lim, S. T., Ota, N., Schlaepfer, D. D. and Ilic, D. (2008). FAK nuclear export signal sequences. FEBS Lett, 582: 2402–2406

    Google Scholar 

  • Parsons J T (2003). Focal adhesion kinase: the first ten years. J Cell Sci, 116(Pt 8):1409–1416

    Article  CAS  PubMed  Google Scholar 

  • Peng X, Guan J L (2011). Focal adhesion kinase: from in vitro studies to functional analyses in vivo. Curr Protein Pept Sci, 12(1): 52–67

    Article  CAS  PubMed  Google Scholar 

  • Peng X, Kraus M S, Wei H, Shen T L, Pariaut R, Alcaraz A, Ji G, Cheng L, Yang Q, Kotlikoff M I, Chen J, Chien K, Gu H, Guan J L (2006). Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice. J Clin Invest, 116(1): 217–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ray B J, Thomas K, Huang C S, GutknechtMF, Botchwey E A, Bouton A H (2012). Regulation of osteoclast structure and function by FAK family kinases. J Leukoc Biol, 92(5): 1021–1028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richardson A, Parsons T (1996). A mechanism for regulation of the adhesion-associated proteintyrosine kinase pp125FAK. Nature, 380 (6574): 538–540

    Article  CAS  PubMed  Google Scholar 

  • Sasaki H, Nagura K, Ishino M, Tobioka H, Kotani K, Sasaki T (1995). Cloning and characterization of cell adhesion kinase beta, a novel protein-tyrosine kinase of the focal adhesion kinase subfamily. J Biol Chem, 270(36): 21206–21219

    Article  CAS  PubMed  Google Scholar 

  • Sayers R L, Sundberg-Smith L J, Rojas M, Hayasaka H, Parsons J T, Mack C P, Taylor J M (2008). FRNK expression promotes smooth muscle cell maturation during vascular development and after vascular injury. Arterioscler Thromb Vasc Biol, 28(12): 2115–2122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schlaepfer D D, Hauck C R, Sieg D J (1999). Signaling through focal adhesion kinase. Prog Biophys Mol Biol, 71(3-4): 435–478

    Article  CAS  PubMed  Google Scholar 

  • Serrels A, Lund T, Serrels B, Byron A, McPherson R C, von Kriegsheim A, Gómez-Cuadrado L, Canel M, Muir M, Ring J E, Maniati E, Sims A H, Pachter J A, Brunton V G, Gilbert N, Anderton S M, Nibbs R J, Frame M C (2015). Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell, 163(1): 160–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shahrara S, Castro-Rueda H P, Haines G K, Koch A E (2007). Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissues. Arthritis Res Ther, 9(5): R112

    Article  PubMed  PubMed Central  Google Scholar 

  • Shelef M A, Bennin D A, Yasmin N, Warner T F, Ludwig T, Beggs H E, Huttenlocher A (2014). Focal adhesion kinase is required for synovial fibroblast invasion, but not murine inflammatory arthritis. Arthritis Res Ther, 16(5): 464

    Article  PubMed  PubMed Central  Google Scholar 

  • Shen T L, Park A Y, Alcaraz A, Peng X, Jang I, Koni P, Flavell R A, Gu H, Guan J L (2005). Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. J Cell Biol, 169(6): 941–952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song M Y, Tian F F, Wang Y Z, Huang X, Guo J L, Ding D X (2015). Potential roles of the RGMa-FAK-Ras pathway in hippocampal mossy fiber sprouting in the pentylenetetrazole kindling model. Mol Med Rep, 11(3): 1738–1744

    CAS  PubMed  PubMed Central  Google Scholar 

  • Suda T, Nakamura I, Jimi E, Takahashi N (1997). Regulation of osteoclast function. J Bone Miner Res, 12(6): 869–879

    Article  CAS  PubMed  Google Scholar 

  • Sulzmaier F J, Jean C, Schlaepfer D D (2014). FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer, 14(9): 598–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tavora B, Reynolds L E, Batista S, Demircioglu F, Fernandez I, Lechertier T, Lees D M, Wong P P, Alexopoulou A, Elia G, Clear A, Ledoux A, Hunter J, Perkins N, Gribben J G, Hodivala-Dilke K M (2014). Endothelial-cell FAK targeting sensitizes tumours to DNAdamaging therapy. Nature, 514(7520): 112–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor J M, Mack C P, Nolan K, Regan C P, Owens G K, Parsons J T (2001). Selective expression of an endogenous inhibitor of FAK regulates proliferation and migration of vascular smooth muscle cells. Mol Cell Biol, 21(5): 1565–1572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor J M, Rovin J D, Parsons J T (2000). A role for focal adhesion kinase in phenylephrine-induced hypertrophy of rat ventricular cardiomyocytes. J Biol Chem, 275(25): 19250–19257

    Article  CAS  PubMed  Google Scholar 

  • Wendt M K, Schiemann B J, Parvani J G, Lee Y H, Kang Y, Schiemann W P (2013). TGF-ß stimulates Pyk2 expression as part of an epithelial-mesenchymal transition program required for metastatic outgrowth of breast cancer. Oncogene, 32(16): 2005–2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wynn T A (2011). Integrating mechanisms of pulmonary fibrosis. J Exp Med, 208(7): 1339–1350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong W C, Macklem M, Parsons J T (1998). Expression and characterization of splice variants of PYK2, a focal adhesion kinase-related protein. J Cell Sci, 111(Pt 14): 1981–1991

    CAS  PubMed  Google Scholar 

  • Yoon H, Dehart J P, Murphy J M, Lim S T (2015). Understanding the roles of FAK in cancer: inhibitors, genetic models, and new insights. J Histochem Cytochem, 63(2): 114–128

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao J, Guan J L (2009). Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev, 28(1-2): 35–49

    Article  PubMed  Google Scholar 

  • Zhou J, Aponte-Santamaría C, Sturm S, Bullerjahn J T, Bronowska A, Gräter F (2015). Mechanism of Focal Adhesion Kinase Mechanosensing. PLOS Comput Biol, 11(11): e1004593

    Article  Google Scholar 

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  1. Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama, 36688, USA

    James M. Murphy, Hyeonsoo Park & Ssang-Taek Steve Lim

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  1. James M. Murphy
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  2. Hyeonsoo Park
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Murphy, J.M., Park, H. & Lim, ST.S. FAK and Pyk2 in disease. Front. Biol. 11, 1–9 (2016). https://doi.org/10.1007/s11515-016-1384-4

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