Focal adhesion kinase signaling in cardiac hypertrophy and failure

Franchini, K.G.; Clemente, C.F.M.Z.; Marin, T.M.

doi:10.1590/S0100-879X2009000100008

Abstract

Focal adhesion kinase (FAK) is a broadly expressed tyrosine kinase implicated in cellular functions such as migration, growth and survival. Emerging data support a role for FAK in cardiac development, reactive hypertrophy and failure. Data reviewed here indicate that FAK plays a critical role at the cellular level in the responses of cardiomyocytes and cardiac fibroblasts to biomechanical stress and to hypertrophic agonists such as angiotensin II and endothelin. The signaling mechanisms regulated by FAK are discussed to provide insight into its role in the pathophysiology of cardiac hypertrophy and failure.

Focal adhesion kinase; Mechanical signaling; Cardiovascular system; Signal transduction

Braz J Med Biol Res, January 2009, Volume 42(1) 44-52

Focal adhesion kinase signaling in cardiac hypertrophy and failure

K.G. Franchini, C.F.M.Z. Clemente and T.M. Marin

Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil

Text

References Correspondence and Footnotes

Abstract

Focal adhesion kinase (FAK) is a broadly expressed tyrosine kinase implicated in cellular functions such as migration, growth and survival. Emerging data support a role for FAK in cardiac development, reactive hypertrophy and failure. Data reviewed here indicate that FAK plays a critical role at the cellular level in the responses of cardiomyocytes and cardiac fibroblasts to biomechanical stress and to hypertrophic agonists such as angiotensin II and endothelin. The signaling mechanisms regulated by FAK are discussed to provide insight into its role in the pathophysiology of cardiac hypertrophy and failure.

Figure 2. Ventricular adult cardiomyocyte fluorescent imaging. A, Anti-focal adhesion kinase (FAK) staining in green. B, Phalloidin staining in red. C, Merge anti-FAK/phalloidin.

Figure 3. Focal adhesion kinase (FAK) depletion impairs the hypertrophic responses of cardiomyocytes to mechanical stress (A, non-stimulated; B, stretched _ 24 h; C, depleted of FAK and stretched cardiomyocyte; bar = 10 µm for panels A-C). D, High magnification (1200X) of anti-FAK myocardial staining (yellowish) from 12-week banded mice highlighting an area of focal myocardial fibrosis. E, Low magnification (400X) of anti-FAK staining from a myocardial biopsy taken from a patient with heart failure due to mitral regurgitation. F, Low magnification (400X) of Masson trichrome staining (green) from 6-week banded mice treated with an irrelevant small interfering RNA (siRNA) targeted to green fluorescent protein. G, Low magnification (400X) of Masson trichrome staining from a 6-week banded mouse treated with siRNA targeted to FAK.

1. Kong SW, Bodyak N, Yue P, Liu Z, Brown J, Izumo S, et al. Genetic expression profiles during physiological and pathological cardiac hypertrophy and heart failure in rats. Physiol Genomics 2005; 21: 34-42.
2. Parsons JT. Focal adhesion kinase: the first ten years. J Cell Sci 2003; 116: 1409-1416.
3. Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 2005; 6: 56-68.
4. Lietha D, Cai X, Ceccarelli DF, Li Y, Schaller MD, Eck MJ. Structural basis for the autoinhibition of focal adhesion kinase. Cell 2007; 129: 1177-1187.
5. Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT. Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol 1994; 14: 1680-1688.
6. Cooper LA, Shen TL, Guan JL. Regulation of focal adhesion kinase by its amino-terminal domain through an autoinhibitory interaction. Mol Cell Biol 2003; 23: 8030-8041.
7. Cai X, Lietha D, Ceccarelli DF, Karginov AV, Rajfur Z, Jacobson K, et al. Spatial and temporal regulation of focal adhesion kinase activity in living cells. Mol Cell Biol 2008; 28: 201-214.
8. Dunty JM, Gabarra-Niecko V, King ML, Ceccarelli DF, Eck MJ, Schaller MD. FERM domain interaction promotes FAK signaling. Mol Cell Biol 2004; 24: 5353-5368.
9. Calalb MB, Polte TR, Hanks SK. Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Mol Cell Biol 1995; 15: 954-963.
10. Schlaepfer DD, Hanks SK, Hunter T, van der Geer P. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 1994; 372: 786-791.
11. Tachibana K, Urano T, Fujita H, Ohashi Y, Kamiguchi K, Iwata S, et al. Tyrosine phosphorylation of Crk-associated substrates by focal adhesion kinase. A putative mechanism for the integrin-mediated tyrosine phosphorylation of Crk-associated substrates. J Biol Chem 1997; 272: 29083-29090.
12. Schaller MD, Parsons JT. pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk. Mol Cell Biol 1995; 15: 2635-2645.
13. Renshaw MW, Price LS, Schwartz MA. Focal adhesion kinase mediates the integrin signaling requirement for growth factor activation of MAP kinase. J Cell Biol 1999; 147: 611-618.
14. Chen HC, Appeddu PA, Isoda H, Guan JL. Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidyl inositol 3-kinase. J Biol Chem 1996; 271: 26329-26334.
15. Akagi T, Murata K, Shishido T, Hanafusa H. v-Crk activates the phosphoinositide 3-kinase/AKT pathway by utilizing focal adhesion kinase and H-Ras. Mol Cell Biol 2002; 22: 7015-7023.
16. Franchini KG, Torsoni AS, Soares PH, Saad MJ. Early activation of the multicomponent signaling complex associated with focal adhesion kinase induced by pressure overload in the rat heart. Circ Res 2000; 87: 558-565.
17. Torsoni AS, Constancio SS, Nadruz W Jr, Hanks SK, Franchini KG. Focal adhesion kinase is activated and mediates the early hypertrophic response to stretch in cardiac myocytes. Circ Res 2003; 93: 140-147.
18. Torsoni AS, Marin TM, Velloso LA, Franchini KG. RhoA/ROCK signaling is critical to FAK activation by cyclic stretch in cardiac myocytes. Am J Physiol Heart Circ Physiol 2005; 289: H1488-H1496.
19. Nadruz W Jr, Corat MA, Marin TM, Guimaraes Pereira GA, Franchini KG. Focal adhesion kinase mediates MEF2 and c-Jun activation by stretch: role in the activation of the cardiac hypertrophic genetic program. Cardiovasc Res 2005; 68: 87-97.
20. Eble DM, Strait JB, Govindarajan G, Lou J, Byron KL, Samarel AM. Endothelin-induced cardiac myocyte hypertrophy: role for focal adhesion kinase. Am J Physiol Heart Circ Physiol 2000; 278: H1695-H1707.
21. Taylor JM, Rovin JD, Parsons JT. A role for focal adhesion kinase in phenylephrine-induced hypertrophy of rat ventricular cardiomyocytes. J Biol Chem 2000; 275: 19250-19257.
22. Domingos PP, Fonseca PM, Nadruz W Jr, Franchini KG. Load-induced focal adhesion kinase activation in the myocardium: role of stretch and contractile activity. Am J Physiol Heart Circ Physiol 2002; 282: H556-H564.
23. Fonseca PM, Inoue RY, Kobarg CB, Crosara-Alberto DP, Kobarg J, Franchini KG. Targeting to C-terminal myosin heavy chain may explain mechanotransduction involving focal adhesion kinase in cardiac myocytes. Circ Res 2005; 96: 73-81.
24. Heidkamp MC, Bayer AL, Kalina JA, Eble DM, Samarel AM. GFP-FRNK disrupts focal adhesions and induces anoikis in neonatal rat ventricular myocytes. Circ Res 2002; 90: 1282-1289.
25. Katz BZ, Miyamoto S, Teramoto H, Zohar M, Krylov D, Vinson C, et al. Direct transmembrane clustering and cytoplasmic dimerization of focal adhesion kinase initiates its tyrosine phosphorylation. Biochim Biophys Acta 2002; 1592: 141-152.
26. Heidkamp MC, Bayer AL, Scully BT, Eble DM, Samarel AM. Activation of focal adhesion kinase by protein kinase C epsilon in neonatal rat ventricular myocytes. Am J Physiol Heart Circ Physiol 2003; 285: H1684-H1696.
27. Marin TM, Clemente CF, Santos AM, Picardi PK, Pascoal VD, Lopes-Cendes I, et al. Shp2 negatively regulates growth in cardiomyocytes by controlling focal adhesion kinase/Src and mTOR pathways. Circ Res 2008; 103: 813-824.
28. von Wichert G, Haimovich B, Feng GS, Sheetz MP. Force-dependent integrin-cytoskeleton linkage formation requires downregulation of focal complex dynamics by Shp2. EMBO J 2003; 22: 5023-5035.
29. Xu F, Zhao R, Peng Y, Guerrah A, Zhao ZJ. Association of tyrosine phosphatase SHP-2 with F-actin at low cell densities. J Biol Chem 2001; 276: 29479-29484.
30. Schoenwaelder SM, Petch LA, Williamson D, Shen R, Feng GS, Burridge K. The protein tyrosine phosphatase Shp-2 regulates RhoA activity. Curr Biol 2000; 10: 1523-1526.
31. Cobb BS, Schaller MD, Leu TH, Parsons JT. Stable association of pp60src and pp59fyn with the focal adhesion-associated protein tyrosine kinase, pp125FAK. Mol Cell Biol 1994; 14: 147-155.
32. Yi XP, Zhou J, Huber L, Qu J, Wang X, Gerdes AM, et al. Nuclear compartmentalization of FAK and FRNK in cardiac myocytes. Am J Physiol Heart Circ Physiol 2006; 290: H2509-H2515.
33. Senyo SE, Koshman YE, Russell B. Stimulus interval, rate and direction differentially regulate phosphorylation for mechanotransduction in neonatal cardiac myocytes. FEBS Lett 2007; 581: 4241-4247.
34. Lim ST, Chen XL, Lim Y, Hanson DA, Vo TT, Howerton K, et al. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell 2008; 29: 9-22.
35. Golubovskaya VM, Finch R, Zheng M, Kurenova EV, Cance WG. The 7-amino-acid site in the proline-rich region of the N-terminal domain of p53 is involved in the interaction with FAK and is critical for p53 functioning. Biochem J 2008; 411: 151-160.
36. Hakuno D, Takahashi T, Lammerding J, Lee RT. Focal adhesion kinase signaling regulates cardiogenesis of embryonic stem cells. J Biol Chem 2005; 280: 39534-39544.
37. Hakim ZS, DiMichele LA, Doherty JT, Homeister JW, Beggs HE, Reichardt LF, et al. Conditional deletion of focal adhesion kinase leads to defects in ventricular septation and outflow tract alignment. Mol Cell Biol 2007; 27: 5352-5364.
38. Peng X, Wu X, Druso JE, Wei H, Park AY, Kraus MS, et al. Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocyte focal adhesion kinase (FAK) conditional knockout mice. Proc Natl Acad Sci U S A 2008; 105: 6638-6643.
39. Pham CG, Harpf AE, Keller RS, Vu HT, Shai SY, Loftus JC, et al. Striated muscle-specific beta(1D)-integrin and FAK are involved in cardiac myocyte hypertrophic response pathway. Am J Physiol Heart Circ Physiol 2000; 279: H2916-H2926.
40. Clerk A, Cullingford TE, Fuller SJ, Giraldo A, Markou T, Pikkarainen S, et al. Signaling pathways mediating cardiac myocyte gene expression in physiological and stress responses. J Cell Physiol 2007; 212: 311-322.
41. Hanks SK, Ryzhova L, Shin NY, Brabek J. Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility. Front Biosci 2003; 8: d982-d996.
42. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10: 151-162.
43. Gan B, Yoo Y, Guan JL. Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth. J Biol Chem 2006; 281: 37321-37329.
44. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 2002; 110: 737-749.
45. Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, et al. Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol 2002; 22: 2799-2809.
46. Olson EN, Schneider MD. Sizing up the heart: development redux in disease. Genes Dev 2003; 17: 1937-1956.
47. Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 1995; 377: 539-544.
48. Furuta Y, Ilic D, Kanazawa S, Takeda N, Yamamoto T, Aizawa S. Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK. Oncogene 1995; 11: 1989-1995.
49. Clemente CF, Corat MA, Saad ST, Franchini KG. Differentiation of C2C12 myoblasts is critically regulated by FAK signaling. Am J Physiol Regul Integr Comp Physiol 2005; 289: R862-R870.
50. Sastry SK, Lakonishok M, Wu S, Truong TQ, Huttenlocher A, Turner CE, et al. Quantitative changes in integrin and focal adhesion signaling regulate myoblast cell cycle withdrawal. J Cell Biol 1999; 144: 1295-1309.
51. Peng X, Kraus MS, Wei H, Shen TL, Pariaut R, Alcaraz A, et al. Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice. J Clin Invest 2006; 116: 217-227.
52. DiMichele LA, Doherty JT, Rojas M, Beggs HE, Reichardt LF, Mack CP, et al. Myocyte-restricted focal adhesion kinase deletion attenuates pressure overload-induced hypertrophy. Circ Res 2006; 99: 636-645.
53. Clemente CF, Tornatore TF, Theizen TH, Deckmann AC, Pereira TC, Lopes-Cendes I, et al. Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice. Circ Res 2007; 101: 1339-1348.
54. Bayer AL, Heidkamp MC, Patel N, Porter MJ, Engman SJ, Samarel AM. PYK2 expression and phosphorylation increases in pressure overload-induced left ventricular hypertrophy. Am J Physiol Heart Circ Physiol 2002; 283: H695-H706.
55. Lopes MM, Ribeiro GC, Tornatore TF, Clemente CF, Teixeira VP, Franchini KG. Increased expression and phosphorylation of focal adhesion kinase correlates with dysfunction in the volume-overloaded human heart. Clin Sci 2007; 113: 195-204.
56. Iwanaga Y, Aoyama T, Kihara Y, Onozawa Y, Yoneda T, Sasayama S. Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats. J Am Coll Cardiol 2002; 39: 1384-1391.

K.G. Franchini, C.F.M.Z. Clemente and T.M. Marin. Focal adhesion kinase signaling in cardiac hypertrophy and failure. Braz J Med Biol Res 2009; 42: 44-52.

Publication Dates

Publication in this collection
12 Feb 2009
Date of issue
Jan 2009

History

Received
08 July 2008
Accepted
11 Dec 2008

This work is licensed under a Creative Commons Attribution 4.0 International License.

[1] 1. Kong SW, Bodyak N, Yue P, Liu Z, Brown J, Izumo S, et al. Genetic expression profiles during physiological and pathological cardiac hypertrophy and heart failure in rats. Physiol Genomics 2005; 21: 34-42.

[2] 2. Parsons JT. Focal adhesion kinase: the first ten years. J Cell Sci 2003; 116: 1409-1416.

[3] 3. Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 2005; 6: 56-68.

[4] 4. Lietha D, Cai X, Ceccarelli DF, Li Y, Schaller MD, Eck MJ. Structural basis for the autoinhibition of focal adhesion kinase. Cell 2007; 129: 1177-1187.

[5] 5. Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT. Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol 1994; 14: 1680-1688.

[6] 6. Cooper LA, Shen TL, Guan JL. Regulation of focal adhesion kinase by its amino-terminal domain through an autoinhibitory interaction. Mol Cell Biol 2003; 23: 8030-8041.

[7] 7. Cai X, Lietha D, Ceccarelli DF, Karginov AV, Rajfur Z, Jacobson K, et al. Spatial and temporal regulation of focal adhesion kinase activity in living cells. Mol Cell Biol 2008; 28: 201-214.

[8] 8. Dunty JM, Gabarra-Niecko V, King ML, Ceccarelli DF, Eck MJ, Schaller MD. FERM domain interaction promotes FAK signaling. Mol Cell Biol 2004; 24: 5353-5368.

[9] 9. Calalb MB, Polte TR, Hanks SK. Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Mol Cell Biol 1995; 15: 954-963.

[10] 10. Schlaepfer DD, Hanks SK, Hunter T, van der Geer P. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature 1994; 372: 786-791.

[11] 11. Tachibana K, Urano T, Fujita H, Ohashi Y, Kamiguchi K, Iwata S, et al. Tyrosine phosphorylation of Crk-associated substrates by focal adhesion kinase. A putative mechanism for the integrin-mediated tyrosine phosphorylation of Crk-associated substrates. J Biol Chem 1997; 272: 29083-29090.

[12] 12. Schaller MD, Parsons JT. pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk. Mol Cell Biol 1995; 15: 2635-2645.

[13] 13. Renshaw MW, Price LS, Schwartz MA. Focal adhesion kinase mediates the integrin signaling requirement for growth factor activation of MAP kinase. J Cell Biol 1999; 147: 611-618.

[14] 14. Chen HC, Appeddu PA, Isoda H, Guan JL. Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidyl inositol 3-kinase. J Biol Chem 1996; 271: 26329-26334.

[15] 15. Akagi T, Murata K, Shishido T, Hanafusa H. v-Crk activates the phosphoinositide 3-kinase/AKT pathway by utilizing focal adhesion kinase and H-Ras. Mol Cell Biol 2002; 22: 7015-7023.

[16] 16. Franchini KG, Torsoni AS, Soares PH, Saad MJ. Early activation of the multicomponent signaling complex associated with focal adhesion kinase induced by pressure overload in the rat heart. Circ Res 2000; 87: 558-565.

[17] 17. Torsoni AS, Constancio SS, Nadruz W Jr, Hanks SK, Franchini KG. Focal adhesion kinase is activated and mediates the early hypertrophic response to stretch in cardiac myocytes. Circ Res 2003; 93: 140-147.

[18] 18. Torsoni AS, Marin TM, Velloso LA, Franchini KG. RhoA/ROCK signaling is critical to FAK activation by cyclic stretch in cardiac myocytes. Am J Physiol Heart Circ Physiol 2005; 289: H1488-H1496.

[19] 19. Nadruz W Jr, Corat MA, Marin TM, Guimaraes Pereira GA, Franchini KG. Focal adhesion kinase mediates MEF2 and c-Jun activation by stretch: role in the activation of the cardiac hypertrophic genetic program. Cardiovasc Res 2005; 68: 87-97.

[20] 20. Eble DM, Strait JB, Govindarajan G, Lou J, Byron KL, Samarel AM. Endothelin-induced cardiac myocyte hypertrophy: role for focal adhesion kinase. Am J Physiol Heart Circ Physiol 2000; 278: H1695-H1707.

[21] 21. Taylor JM, Rovin JD, Parsons JT. A role for focal adhesion kinase in phenylephrine-induced hypertrophy of rat ventricular cardiomyocytes. J Biol Chem 2000; 275: 19250-19257.

[22] 22. Domingos PP, Fonseca PM, Nadruz W Jr, Franchini KG. Load-induced focal adhesion kinase activation in the myocardium: role of stretch and contractile activity. Am J Physiol Heart Circ Physiol 2002; 282: H556-H564.

[23] 23. Fonseca PM, Inoue RY, Kobarg CB, Crosara-Alberto DP, Kobarg J, Franchini KG. Targeting to C-terminal myosin heavy chain may explain mechanotransduction involving focal adhesion kinase in cardiac myocytes. Circ Res 2005; 96: 73-81.

[24] 24. Heidkamp MC, Bayer AL, Kalina JA, Eble DM, Samarel AM. GFP-FRNK disrupts focal adhesions and induces anoikis in neonatal rat ventricular myocytes. Circ Res 2002; 90: 1282-1289.

[25] 25. Katz BZ, Miyamoto S, Teramoto H, Zohar M, Krylov D, Vinson C, et al. Direct transmembrane clustering and cytoplasmic dimerization of focal adhesion kinase initiates its tyrosine phosphorylation. Biochim Biophys Acta 2002; 1592: 141-152.

[26] 26. Heidkamp MC, Bayer AL, Scully BT, Eble DM, Samarel AM. Activation of focal adhesion kinase by protein kinase C epsilon in neonatal rat ventricular myocytes. Am J Physiol Heart Circ Physiol 2003; 285: H1684-H1696.

[27] 27. Marin TM, Clemente CF, Santos AM, Picardi PK, Pascoal VD, Lopes-Cendes I, et al. Shp2 negatively regulates growth in cardiomyocytes by controlling focal adhesion kinase/Src and mTOR pathways. Circ Res 2008; 103: 813-824.

[28] 28. von Wichert G, Haimovich B, Feng GS, Sheetz MP. Force-dependent integrin-cytoskeleton linkage formation requires downregulation of focal complex dynamics by Shp2. EMBO J 2003; 22: 5023-5035.

[29] 29. Xu F, Zhao R, Peng Y, Guerrah A, Zhao ZJ. Association of tyrosine phosphatase SHP-2 with F-actin at low cell densities. J Biol Chem 2001; 276: 29479-29484.

[30] 30. Schoenwaelder SM, Petch LA, Williamson D, Shen R, Feng GS, Burridge K. The protein tyrosine phosphatase Shp-2 regulates RhoA activity. Curr Biol 2000; 10: 1523-1526.

[31] 31. Cobb BS, Schaller MD, Leu TH, Parsons JT. Stable association of pp60src and pp59fyn with the focal adhesion-associated protein tyrosine kinase, pp125FAK. Mol Cell Biol 1994; 14: 147-155.

[32] 32. Yi XP, Zhou J, Huber L, Qu J, Wang X, Gerdes AM, et al. Nuclear compartmentalization of FAK and FRNK in cardiac myocytes. Am J Physiol Heart Circ Physiol 2006; 290: H2509-H2515.

[33] 33. Senyo SE, Koshman YE, Russell B. Stimulus interval, rate and direction differentially regulate phosphorylation for mechanotransduction in neonatal cardiac myocytes. FEBS Lett 2007; 581: 4241-4247.

[34] 34. Lim ST, Chen XL, Lim Y, Hanson DA, Vo TT, Howerton K, et al. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell 2008; 29: 9-22.

[35] 35. Golubovskaya VM, Finch R, Zheng M, Kurenova EV, Cance WG. The 7-amino-acid site in the proline-rich region of the N-terminal domain of p53 is involved in the interaction with FAK and is critical for p53 functioning. Biochem J 2008; 411: 151-160.

[36] 36. Hakuno D, Takahashi T, Lammerding J, Lee RT. Focal adhesion kinase signaling regulates cardiogenesis of embryonic stem cells. J Biol Chem 2005; 280: 39534-39544.

[37] 37. Hakim ZS, DiMichele LA, Doherty JT, Homeister JW, Beggs HE, Reichardt LF, et al. Conditional deletion of focal adhesion kinase leads to defects in ventricular septation and outflow tract alignment. Mol Cell Biol 2007; 27: 5352-5364.

[38] 38. Peng X, Wu X, Druso JE, Wei H, Park AY, Kraus MS, et al. Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocyte focal adhesion kinase (FAK) conditional knockout mice. Proc Natl Acad Sci U S A 2008; 105: 6638-6643.

[39] 39. Pham CG, Harpf AE, Keller RS, Vu HT, Shai SY, Loftus JC, et al. Striated muscle-specific beta(1D)-integrin and FAK are involved in cardiac myocyte hypertrophic response pathway. Am J Physiol Heart Circ Physiol 2000; 279: H2916-H2926.

[40] 40. Clerk A, Cullingford TE, Fuller SJ, Giraldo A, Markou T, Pikkarainen S, et al. Signaling pathways mediating cardiac myocyte gene expression in physiological and stress responses. J Cell Physiol 2007; 212: 311-322.

[41] 41. Hanks SK, Ryzhova L, Shin NY, Brabek J. Focal adhesion kinase signaling activities and their implications in the control of cell survival and motility. Front Biosci 2003; 8: d982-d996.

[42] 42. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10: 151-162.

[43] 43. Gan B, Yoo Y, Guan JL. Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth. J Biol Chem 2006; 281: 37321-37329.

[44] 44. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 2002; 110: 737-749.

[45] 45. Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, et al. Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol 2002; 22: 2799-2809.

[46] 46. Olson EN, Schneider MD. Sizing up the heart: development redux in disease. Genes Dev 2003; 17: 1937-1956.

[47] 47. Ilic D, Furuta Y, Kanazawa S, Takeda N, Sobue K, Nakatsuji N, et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 1995; 377: 539-544.

[48] 48. Furuta Y, Ilic D, Kanazawa S, Takeda N, Yamamoto T, Aizawa S. Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK. Oncogene 1995; 11: 1989-1995.

[49] 49. Clemente CF, Corat MA, Saad ST, Franchini KG. Differentiation of C2C12 myoblasts is critically regulated by FAK signaling. Am J Physiol Regul Integr Comp Physiol 2005; 289: R862-R870.

[50] 50. Sastry SK, Lakonishok M, Wu S, Truong TQ, Huttenlocher A, Turner CE, et al. Quantitative changes in integrin and focal adhesion signaling regulate myoblast cell cycle withdrawal. J Cell Biol 1999; 144: 1295-1309.

[51] 51. Peng X, Kraus MS, Wei H, Shen TL, Pariaut R, Alcaraz A, et al. Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice. J Clin Invest 2006; 116: 217-227.

[52] 52. DiMichele LA, Doherty JT, Rojas M, Beggs HE, Reichardt LF, Mack CP, et al. Myocyte-restricted focal adhesion kinase deletion attenuates pressure overload-induced hypertrophy. Circ Res 2006; 99: 636-645.

[53] 53. Clemente CF, Tornatore TF, Theizen TH, Deckmann AC, Pereira TC, Lopes-Cendes I, et al. Targeting focal adhesion kinase with small interfering RNA prevents and reverses load-induced cardiac hypertrophy in mice. Circ Res 2007; 101: 1339-1348.

[54] 54. Bayer AL, Heidkamp MC, Patel N, Porter MJ, Engman SJ, Samarel AM. PYK2 expression and phosphorylation increases in pressure overload-induced left ventricular hypertrophy. Am J Physiol Heart Circ Physiol 2002; 283: H695-H706.

[55] 55. Lopes MM, Ribeiro GC, Tornatore TF, Clemente CF, Teixeira VP, Franchini KG. Increased expression and phosphorylation of focal adhesion kinase correlates with dysfunction in the volume-overloaded human heart. Clin Sci 2007; 113: 195-204.

[56] 56. Iwanaga Y, Aoyama T, Kihara Y, Onozawa Y, Yoneda T, Sasayama S. Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats. J Am Coll Cardiol 2002; 39: 1384-1391.