Skip to main content

Advertisement

SpringerLink
Log in

Recent advances of adapter proteins in the regulation of heart diseases

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Heart diseases are major causes of mortality. Cardiac hypertrophy, myocardial infarction (MI), viral cardiomyopathy, ischemic and reperfusion (I/R) heart injury finally lead to heart failure and death. Insulin and IGF1 signal pathways play key roles in normal cardiomyocyte growth and physiological cardiac hypertrophy while inflammatory signal pathway is associated with pathological cardiac hypertrophy, MI, viral cardiomyopathy, I/R heart injury, and heart failure. Adapter proteins are the major family proteins, which transduce signals from insulin, IGF1, or cytokine receptors to the downstream pathways and have been shown to regulate variety of heart diseases. Here, we summarized the recent advances in understanding the physiological and pathological roles of adapter proteins in heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Heidenreich PA et al (2011) Forecasting the future of cardiovascular disease in the United States a policy statement from the American Heart Association. Circulation 123(8):933–944

    Article  PubMed  Google Scholar 

  2. McMullen JR et al (2004) The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110α) pathway. J Biol Chem 279(6):4782–4793

    Article  CAS  PubMed  Google Scholar 

  3. Bugger H et al (2012) Genetic loss of insulin receptors worsens cardiac efficiency in diabetes. J Mol Cell Cardiol 52(5):1019–1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Qi Y et al (2013) Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38α MAPK during insulin resistance. Diabetes 62(11):3887–3900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. McMullen JR (2008) Role of insulin-like growth factor 1 and phosphoinositide 3-kinase in a setting of heart disease. Clin Exp Pharmacol Physiol 35(3):349–354

    Article  CAS  PubMed  Google Scholar 

  6. Li Q et al (1997) Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Investig 100(8):1991–1999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. McMullen JR et al (2007) Protective effects of exercise and phosphoinositide 3-kinase(p110α) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci USA 104(2):612–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Riehle C et al (2014) Insulin receptor substrates are essential for the bioenergetic and hypertrophic response of the heart to exercise training. Mol Cell Biol 34(18):3450–3460

    Article  PubMed  PubMed Central  Google Scholar 

  9. Vinciguerra M et al (2012) mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart. Aging Cell 11(1):139–149

    Article  CAS  PubMed  Google Scholar 

  10. Arslan F, de Kleijn DP, Pasterkamp G (2011) Innate immune signaling in cardiac ischemia. Nat Rev Cardiol 8(5):292–300

    Article  CAS  PubMed  Google Scholar 

  11. Blauwet LA, Cooper LT (2010) Myocarditis. Prog Cardiovasc Dis 52(4):274–288

    Article  PubMed  Google Scholar 

  12. Mezzaroma E et al (2011) The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci USA 108(49):19725–19730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang Y et al (2016) The emerging role of toll-like receptor 4 in myocardial inflammation. Cell Death Dis 7(5):e2234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Avlas O et al (2010) Toll-like receptor 4 stimulation initiates an inflammatory response that decreases cardiomyocyte contractility. Antioxid Redox Signal 15(7):1895–1909

    Article  Google Scholar 

  15. Fallach R et al (2010) Cardiomyocyte toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia. J Mol Cell Cardiol 48(6):1236–1244

    Article  CAS  PubMed  Google Scholar 

  16. Leo A et al (2002) Adapters in lymphocyte signaling. J Clin Invest 109(3):301–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pawson T, Scott JD (1997) Signaling through scaffold, anchoring, and adaptor proteins. Science 278(5346):2075–2080

    Article  CAS  PubMed  Google Scholar 

  18. Bradley JR, Pober JS (2001) Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene 20(44):6482–6491

    Article  CAS  PubMed  Google Scholar 

  19. Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7(6):454–465

    Article  CAS  PubMed  Google Scholar 

  20. Chen Z (2016) Adapter proteins regulate insulin resistance and lipid metabolism in obesity. Sci Bull. doi:10.1007/s11434-016-1058-2

  21. Tao L et al (2015) Exercise for the heart: signaling pathways. Oncotarget 6(25):20773–20784

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kolwicz SC, Purohit S, Tian R (2013) Cardiac metabolism and its interactions with contraction, growth, and survival of the cardiomyocte. Circ Res. doi:10.1161/CIRCRESAHA.113.302095

    PubMed  PubMed Central  Google Scholar 

  23. Dikow R et al (2009) Effect of insulin and glucose infusion on myocardial infarction size in uraemic rats. Basic Res Cardiol 104(5):571–579

    Article  CAS  PubMed  Google Scholar 

  24. Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414(6865):799–806

    Article  CAS  PubMed  Google Scholar 

  25. Du Y, Wei T (2014) Inputs and outputs of insulin receptor. Protein Cell 5(3):203–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ravichandran KS (2001) Signaling via Shc family adapter proteins. Oncogene 20(44):6322–6330

    Article  CAS  PubMed  Google Scholar 

  27. Obreztchikova M et al (2006) Distinct signaling functions for Shc isoforms in the heart. J Biol Chem 281(29):20197–20204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cesselli D et al (2001) Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. Circ Res 89(3):279–286

    Article  CAS  PubMed  Google Scholar 

  29. Giorgio M et al (2005) Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122(2):221–233

    Article  CAS  PubMed  Google Scholar 

  30. Pani G (2010) P66SHC and ageing: ROS and TOR? Aging (Albany NY) 2(8):514–518

    Article  CAS  Google Scholar 

  31. Camici GG et al (2007) Genetic deletion of p66(Shc) adaptor protein prevents hyperglycemia-induced endothelial dysfunction and oxidative stress. Proc Natl Acad Sci USA 104(12):5217–5222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Graiani G et al (2005) Genetic deletion of the p66Shc adaptor protein protects from angiotensin II—induced myocardial damage. Hypertension 46(2):433–440

    Article  CAS  PubMed  Google Scholar 

  33. Diogo CV et al (2013) Cardiac mitochondrial dysfunction during hyperglycemia—the role of oxidative stress and p66Shc signaling. Int J Biochem Cell Biol 45(1):114–122

    Article  CAS  PubMed  Google Scholar 

  34. Di Lisa F et al (2009) Mitochondrial pathways for ROS formation and myocardial injury: the relevance of p66Shc and monoamine oxidase. Basic Res Cardiol 104(2):131–139

    Article  PubMed  Google Scholar 

  35. Baysa A et al (2015) The p66ShcA adaptor protein regulates healing after myocardial infarction. Basic Res Cardiol 110(2):13

    Article  PubMed  Google Scholar 

  36. Akhmedov A et al (2015) Genetic deletion of the adaptor protein p66(Shc) increases susceptibility to short-term ischaemic myocardial injury via intracellular salvage pathways. Eur Heart J 36(8):516-U79

    Article  Google Scholar 

  37. Dance M et al (2006) The adaptor protein Gab1 couples the stimulation of vascular endothelial growth factor receptor-2 to the activation of phosphoinositide 3-kinase. J Biol Chem 281(32):23285–23295

    Article  CAS  PubMed  Google Scholar 

  38. Sun Y et al (2004) Role of Gab1 in UV-induced c-Jun NH2-terminal kinase activation and cell apoptosis. Mol Cell Biol 24(4):1531–1539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Holgado-Madruga M, Wong AJ (2003) Gab1 is an integrator of cell death versus cell survival signals in oxidative stress. Mol Cell Biol 23(13):4471–4484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Itoh M et al (2000) Role of Gab1 in heart, placenta, and skin development and growth factor- and cytokine-induced extracellular signal-regulated kinase mitogen-activated protein kinase activation. Mol Cell Biol 20(10):3695–3704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sachs M et al (2000) Essential role of Gab1 for signaling by the c-Met receptor in vivo. J Cell Biol 150(6):1375–1384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nakaoka Y et al (2007) Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling. J Clin Investig 117(7):1771–1781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao J et al (2016) Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis. Cell Death Differ 23(4):695–706

    Article  CAS  PubMed  Google Scholar 

  44. Sun L et al (2014) Grb2-associated binder 1 is essential for cardioprotection against ischemia/reperfusion injury. Basic Res Cardiol 109(4):1–15

    Article  CAS  Google Scholar 

  45. Rui L (2014) SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 5(4):511–526

    Article  PubMed  PubMed Central  Google Scholar 

  46. Morris DL et al (2009) SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins. Diabetes 58(9):2039–2047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Duan C et al (2004) Disruption of the SH2-B gene causes age-dependent insulin resistance and glucose intolerance. Mol Cell Biol 24(17):7435–7443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ren D et al (2005) Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metab 2(2):95–104

    Article  CAS  PubMed  Google Scholar 

  49. Ren D et al (2007) Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. J Clin Invest 117(2):397–406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen Z et al (2014) SH2B1 in beta-cells regulates glucose metabolism by promoting beta-cell survival and islet expansion. Diabetes 63(2):585–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen Z et al (2014) SH2B1 in beta-cells promotes insulin expression and glucose metabolism in mice. Mol Endocrinol 28(5):696–705

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wu G et al (2015) SH2B1 is critical for the regulation of cardiac remodelling in response to pressure overload. Cardiovasc Res 107(2):203–215

    Article  CAS  PubMed  Google Scholar 

  53. Gery S, Koeffler HP (2013) Role of the adaptor protein LNK in normal and malignant hematopoiesis. Oncogene 32(26):3111–3118

    Article  CAS  PubMed  Google Scholar 

  54. Devallière J, Charreau B (2011) The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling. Biochem Pharmacol 82(10):1391–1402

    Article  PubMed  Google Scholar 

  55. Gudbjartsson DF et al (2009) Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 41(3):342–347

    Article  CAS  PubMed  Google Scholar 

  56. Flister MJ et al (2015) SH2B3 is a genetic determinant of cardiac inflammation and fibrosis. Circ Cardiovasc Genet 8(2):294

    Article  CAS  PubMed  Google Scholar 

  57. Mitsuuchi Y et al (1999) Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2. Oncogene 18(35):4891–4898

    Article  CAS  PubMed  Google Scholar 

  58. Fang X et al (2010) An APPL1-AMPK signaling axis mediates beneficial metabolic effects of adiponectin in the heart. Am J Physiol Endocrinol Metab 299(5):E721–E729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dadson K et al (2016) Cellular, structural and functional cardiac remodelling following pressure overload and unloading. Int J Cardiol 216:32–42

    Article  PubMed  Google Scholar 

  60. Cao T et al (2014) AdipoR1/APPL1 potentiates the protective effects of globular adiponectin on angiotensin II-induced cardiac hypertrophy and fibrosis in neonatal rat atrial myocytes and fibroblasts. PLoS ONE 9(8):e103793

    Article  PubMed  PubMed Central  Google Scholar 

  61. Park M et al (2013) APPL1 transgenic mice are protected from high-fat diet-induced cardiac dysfunction. Am J Physiol Endocrinol Metab 305(7):E795–E804

    Article  CAS  PubMed  Google Scholar 

  62. Yasukawa H et al (2012) SOCS3: a novel therapeutic target for cardioprotection. JAK-STAT 1(4):234–240

    Article  PubMed  PubMed Central  Google Scholar 

  63. Cittadini A et al (2012) SOCS1 gene transfer accelerates the transition to heart failure through the inhibition of the gp130/JAK/STAT pathway. Cardiovasc Res 96(3):381–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yasukawa H et al (2001) Suppressor of cytokine signaling-3 is a biomechanical stress–inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways. J Clin Investig 108(10):1459–1467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yajima T et al (2011) Absence of SOCS3 in the cardiomyocyte increases mortality in a gp130 dependent manner accompanied by contractile dysfunction and ventricular arrhythmias. Circulation 124(24):2690–2701

    Article  PubMed  PubMed Central  Google Scholar 

  66. Oba T et al (2012) Cardiac-specific deletion of SOCS-3 prevents development of left ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol 59(9):838–852

    Article  CAS  PubMed  Google Scholar 

  67. Knowlton KU (2008) CVB infection and mechanisms of viral cardiomyopathy. Curr Top Microbiol Immunol 323:315–335

    CAS  PubMed  Google Scholar 

  68. Yasukawa H et al (2003) The suppressor of cytokine signaling-1 (SOCS1) is a novel therapeutic target for enterovirus-induced cardiac injury. J Clin Invest 111(4):469–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yajima T et al (2006) Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling. Circulation 114(22):2364–2373

    Article  CAS  PubMed  Google Scholar 

  70. Tsygankov AY et al (2001) Beyond the RING: CBL proteins as multivalent adapters. Oncogene 20(44):6382–6402

    Article  CAS  PubMed  Google Scholar 

  71. Rafiq K et al (2014) c-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia. Circulation 129(20):2031–2043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Rafiq K et al (2012) c-Cbl ubiquitin ligase regulates focal adhesion protein turnover and myofibril degeneration induced by neutrophil protease cathepsin G. J Biol Chem 287(8):5327–5339

    Article  CAS  PubMed  Google Scholar 

  73. Valaperti A et al (2014) The adapter protein c-Cbl-associated protein (CAP) protects from acute CVB3-mediated myocarditis through stabilization of type I interferon production and reduced cytotoxicity. Basic Res Cardiol 109(3):1–14

    Article  CAS  Google Scholar 

  74. Chung JY et al (2002) All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci 115(Pt 4):679–688

    CAS  PubMed  Google Scholar 

  75. Chen Z et al (2012) Hepatic TRAF2 regulates glucose metabolism through enhancing glucagon responses. Diabetes 61(3):566–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen Z et al (2015) Hepatocyte TRAF3 promotes insulin resistance and type 2 diabetes in mice with obesity. Mol Metab 4(12):951–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chen Z et al (2015) Myeloid cell TRAF3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity. Am J Physiol Endocrinol Metab 308(6):E460–E469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Huang Y et al (2014) Cardiac-specific Traf2 overexpression enhances cardiac hypertrophy through activating AKT/GSK3β signaling. Gene 536(2):225–231

    Article  CAS  PubMed  Google Scholar 

  79. Divakaran VG et al (2013) Tumor necrosis factor receptor associated factor 2 signaling provokes adverse cardiac remodeling in the adult mammalian heart. Circ Heart Fail 6(3):535–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Tzeng HP et al (2014) Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury. J Am Heart Assoc Cardiovasc Cerebrovasc Dis 3(1):e000662

    Article  Google Scholar 

  81. Jiang X et al (2015) Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy. Hypertension 66(2):356–367

    Article  CAS  PubMed  Google Scholar 

  82. Deguine J, Barton GM (2014) MyD88: a central player in innate immune signaling. F100Prime Rep 6:97

    Article  Google Scholar 

  83. Ha T et al (2005) Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload. Cardiovasc Res 68(2):224–234

    Article  CAS  PubMed  Google Scholar 

  84. Vilahur G et al (2011) Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction. J Mol Cell Cardiol 50(3):522–533

    Article  CAS  PubMed  Google Scholar 

  85. Riad A et al (2008) Toll-like receptor-4 modulates survival by induction of left ventricular remodeling after myocardial infarction in mice. J Immunol 180(10):6954–6961

    Article  CAS  PubMed  Google Scholar 

  86. Oyama J et al (2004) Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation 109(6):784–789

    Article  CAS  PubMed  Google Scholar 

  87. Singh MV et al (2012) MyD88 mediated inflammatory signaling leads to CaMKII oxidation, cardiac hypertrophy and death after myocardial infarction. J Mol Cell Cardiol 52(5):1135–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ha T et al (2006) Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo. Am J Physiol Heart Circ Physiol 290(3):H985–H994

  89. Blyszczuk P et al (2009) Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy. Circ Res 105(9):912–920

    Article  CAS  PubMed  Google Scholar 

  90. Zhu Y et al (2011) The TIR/BB-loop mimetic AS-1 prevents cardiac hypertrophy by inhibiting IL-1R-mediated MyD88-dependent signaling. Basic Res Cardiol 106(5):787–799

    Article  CAS  PubMed  Google Scholar 

  91. Singh MV et al (2015) Dual activation of TRIF and MyD88 adaptor proteins by angiotensin II evokes opposing effects on pressure, cardiac hypertrophy, and inflammatory gene expression. Hypertension 66(3):647–656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Riad A et al (2011) TRIF is a critical survival factor in viral cardiomyopathy. J Immunol 186(4):2561–2570

    Article  CAS  PubMed  Google Scholar 

  93. Chen C et al (2014) Role of extracellular RNA and TLR3-trif signaling in myocardial ischemia-reperfusion injury. J Am Heart Assoc Cardiovasc Cerebrovascu Dis 3(1):e000683

    Article  Google Scholar 

  94. Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116(7):1793–1801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by Changbai Mountain Scholars Program of The People’s Government of Jilin Province 2013046 (to Z. C.), the Jilin Science and Technology Development Program 20160101204JC (to Z. C.), the Jilin Talent Development Foundation 111860000 (to Z. C.), the Fok Ying Tong Education Foundation 151022 (to Z. C.), the National Natural Science Foundation of China Grant 31500957 (to Z. C.), and the startup funds from Northeast Normal University 120401204 (to Z. C.). We apologize to colleagues whose relevant work could not be cited here due to space limitation.

Author information

Authors and Affiliations

  1. Cardiovascular Center, 305 Hospital of People’s Liberation Army, Beijing, 100017, China

    Li Tao, Yuntian Li & Chengyun Song

  2. Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), School of Life Sciences, Northeast Normal University, Changchun, 130024, Jilin, China

    Linna Jia & Zheng Chen

Authors
  1. Li Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linna Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuntian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chengyun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chengyun Song or Zheng Chen.

Ethics declarations

Conflict of interest

L.T., L.J., Y.L., C.S. and Z.C. declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tao, L., Jia, L., Li, Y. et al. Recent advances of adapter proteins in the regulation of heart diseases. Heart Fail Rev 22, 99–107 (2017). https://doi.org/10.1007/s10741-016-9582-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-016-9582-3

Keywords

Search

Navigation