FAK and Pyk2 in disease

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.

Keywords

FAK / Pyk2 / FRNK / disease

References

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

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

[3] 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

[4] 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

[5] 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

[6] 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

[7] 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 W A 3rd, 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 W G, 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

[8] 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

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

[10] 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

[11] Cheng Z, DiMichele 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

[12] 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

[13] 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

[14] DiMichele 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

[15] 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 FAK-dependent manner. J Biol Chem, 283(40): 26839–26849

[16] 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

[17] 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

[18] 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

[19] 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

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

[21] 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

[22] 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

[23] 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). Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening. Curr Biol, 19(18): 1511–1518

[24] 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

[25] 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

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

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

[28] 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

[29] 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

[30] 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

[31] 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

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

[33] 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

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

[35] 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

[36] 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

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

[38] 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

[39] 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

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

[41] 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

[42] 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

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

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

[45] 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

[46] 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

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

[48] 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

[49] 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

[50] 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

[51] 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

[52] 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

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

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

[55] 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 DNA-damaging therapy. Nature, 514(7520): 112–116

[56] 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

[57] 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

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

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

[60] 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

[61] 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

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

[63] 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

Acknowledgements

This work was supported by American Heart Association 12SDG10970000 (to S. L.) and 2013-2015 Abraham Mitchell Cancer Research Fund (to S. L.).

James Murphy, Hyeonsoo Park, and Steve Lim declare that they have no conflict of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg