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cMyBP-C as a promiscuous substrate: phosphorylation by non-PKA kinases and its potential significance

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Abstract

It is now generally accepted that phosphorylation of cMyBP-C is critically important in maintaining normal cardiac function. Although much of the work to date on phospho-regulation of cMyBP-C has focused on the role of protein kinase A (PKA, also known as cAMP-dependent protein kinase), recent evidence suggests that a number of non-PKA serine/threonine kinases, such as Ca2+/calmodulin-dependent protein kinase II, protein kinase C, protein kinase D and the 90-kDa ribosomal S6 kinase are also capable of targeting this key regulatory sarcomeric protein. This article reviews such evidence and proposes a hypothetical role for some of the pertinent signalling pathways in phospho-regulation of cMyBP-C in the setting of heart failure.

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References

  • Avkiran M, Cook AR, Cuello F (2008a) Targeting Na+/H+ exchanger regulation for cardiac protection: a RSKy approach? Curr Opin Pharmacol 8:133–140

    Article  PubMed  CAS  Google Scholar 

  • Avkiran M, Rowland AJ, Cuello F, Haworth RS (2008b) Protein kinase D in the cardiovascular system: emerging roles in health and disease. Circ Res 102:157–163

    Article  PubMed  CAS  Google Scholar 

  • Bardswell SC, Cuello F, Rowland AJ, Sadayappan S, Robbins J, Gautel M, Walker JW, Kentish JC, Avkiran M (2010) Distinct sarcomeric substrates are responsible for protein kinase D-mediated regulation of cardiac myofilament Ca2+ sensitivity and cross-bridge cycling. J Biol Chem 285:5674–5682

    Article  PubMed  CAS  Google Scholar 

  • Barefield D, Sadayappan S (2010) Phosphorylation and function of cardiac myosin binding protein-C in health and disease. J Mol Cell Cardiol 48:866–875

    Article  PubMed  CAS  Google Scholar 

  • Boknik P, Fockenbrock M, Herzig S, Knapp J, Linck B, Luss H, Muller FU, Muller T, Schmitz W, Schroder F, Neumann J (2000) Protein phosphatase activity is increased in a rat model of long-term beta-adrenergic stimulation. Naunyn Schmiedebergs Arch Pharmacol 362:222–231

    Article  PubMed  CAS  Google Scholar 

  • Bossuyt J, Helmstadter K, Wu X, Clements-Jewery H, Haworth RS, Avkiran M, Martin JL, Pogwizd SM, Bers DM (2008) Ca2+/calmodulin-dependent protein kinase IIδ and protein kinase D overexpression reinforce the histone deacetylase 5 redistribution in heart failure. Circ Res 102:695–702

    Article  PubMed  CAS  Google Scholar 

  • Briston SJ, Caldwell JL, Horn MA, Clarke JD, Richards MA, Greensmith DJ, Graham HK, Hall MC, Eisner DA, Dibb KM, Trafford AW (2011) Impaired β-adrenergic responsiveness accentuates dysfunctional excitation-contraction coupling in an ovine model of tachypacing-induced heart failure. J Physiol 589:1367–1382

    Article  PubMed  CAS  Google Scholar 

  • Bristow MR, Minobe W, Rasmussen R, Hershberger RE, Hoffman BB (1988) Alpha-1 adrenergic receptors in the nonfailing and failing human heart. J Pharmacol Exp Ther 247:1039–1045

    PubMed  CAS  Google Scholar 

  • Calalb MB, McKinsey TA, Newkirk S, Huynh K, Sucharov CC, Bristow MR (2009) Increased phosphorylation-dependent nuclear export of class II histone deacetylases in failing human heart. Clin Transl Sci 2:325–332

    Article  PubMed  CAS  Google Scholar 

  • Cazorla O, Szilagyi S, Vignier N, Salazar G, Kramer E, Vassort G, Carrier L, Lacampagne A (2006) Length and protein kinase A modulations of myocytes in cardiac myosin binding protein C-deficient mice. Cardiovasc Res 69:370–380

    Article  PubMed  CAS  Google Scholar 

  • Chen PP, Patel JR, Rybakova IN, Walker JW, Moss RL (2010) Protein kinase A-induced myofilament desensitization to Ca2+ as a result of phosphorylation of cardiac myosin-binding protein C. J Gen Physiol 136:615–627

    Article  PubMed  CAS  Google Scholar 

  • Colson BA, Bekyarova T, Locher MR, Fitzsimons DP, Irving TC, Moss RL (2008) Protein kinase A-mediated phosphorylation of cMyBP-C increases proximity of myosin heads to actin in resting myocardium. Circ Res 103:244–251

    Article  PubMed  CAS  Google Scholar 

  • Copeland O, Sadayappan S, Messer AE, Steinen GJ, van der Velden J, Marston SB (2010) Analysis of cardiac myosin binding protein-C phosphorylation in human heart muscle. J Mol Cell Cardiol 49:1003–1011

    Article  PubMed  CAS  Google Scholar 

  • Cuello F, Bardswell SC, Haworth RS, Yin X, Lutz S, Wieland T, Mayr M, Kentish JC, Avkiran M (2007a) Protein kinase D selectively targets cardiac troponin I and regulates myofilament Ca2+ sensitivity in ventricular myocytes. Circ Res 100:864–873

    Article  PubMed  CAS  Google Scholar 

  • Cuello F, Snabaitis AK, Cohen MS, Taunton J, Avkiran M (2007b) Evidence for direct regulation of myocardial Na+/H+ exchanger isoform 1 phosphorylation and activity by 90-kDa ribosomal S6 kinase (RSK): effects of the novel and specific RSK inhibitor fmk on responses to alpha1-adrenergic stimulation. Mol Pharmacol 71:799–806

    Article  PubMed  CAS  Google Scholar 

  • Cuello F, Bardswell SC, Haworth RS, Ehler E, Sadayappan S, Kentish JC, Avkiran M (2011) Novel role for p90 ribosomal S6 kinase in the regulation of cardiac myofilament phosphorylation. J Biol Chem 286:5300–5310

    Article  PubMed  CAS  Google Scholar 

  • Decker RS, Decker ML, Kulikovskaya I, Nakamura S, Lee DC, Harris K, Klocke FJ, Winegrad S (2005) Myosin-binding protein C phosphorylation, myofibril structure, and contractile function during low-flow ischemia. Circulation 111:906–912

    Article  PubMed  CAS  Google Scholar 

  • El-Armouche A, Eschenhagen T (2009) β-adrenergic stimulation and myocardial function in the failing heart. Heart Fail Rev 14:225–241

    Article  PubMed  CAS  Google Scholar 

  • El-Armouche A, Pohlmann L, Schlossarek S, Starbatty J, Yeh YH, Nattel S, Dobrev D, Eschenhagen T, Carrier L (2007) Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure. J Mol Cell Cardiol 43:223–229

    Article  PubMed  CAS  Google Scholar 

  • Flashman E, Redwood C, Moolman-Smook J, Watkins H (2004) Cardiac myosin binding protein C: its role in physiology and disease. Circ Res 94:1279–1289

    Article  PubMed  CAS  Google Scholar 

  • Gautel M, Zuffardi O, Freiburg A, Labeit S (1995) Phosphorylation switches specific for the cardiac isoform of myosin binding protein-C: a modulator of cardiac contraction? EMBO J 14:1952–1960

    PubMed  CAS  Google Scholar 

  • Goodall MH, Wardlow RD, Goldblum RR, Ziman A, Lederer WJ, Randall W, Rogers TB (2010) Novel function of cardiac protein kinase D1 as a dynamic regulator of Ca2+ sensitivity of contraction. J Biol Chem 285:41686–41700

    Article  PubMed  CAS  Google Scholar 

  • Govindan S, McElligott A, Muthusamy S, Nair N, Barefield D, Martin JL, Gongora E, Greis KD, Luther PK, Winegrad S, Henderson KK, and Sadayappan S (2011) Cardiac myosin binding protein-C is a potential diagnostic biomarker for myocardial infarction. J Mol Cell Cardiol. doi:10.1016/j.yjmcc.2011.09.011

  • Grimm M, Brown JH (2010) β-adrenergic receptor signaling in the heart: role of CaMKII. J Mol Cell Cardiol 48:322–330

    Article  PubMed  CAS  Google Scholar 

  • Gruen M, Prinz H, Gautel M (1999) cAPK-phosphorylation controls the interaction of the regulatory domain of cardiac myosin binding protein C with myosin-S2 in an on-off fashion. FEBS Lett 453:254–259

    Article  PubMed  CAS  Google Scholar 

  • Haworth RS, Goss MW, Rozengurt E, Avkiran M (2000) Expression and activity of protein kinase D/protein kinase C μ in myocardium: evidence for α1-adrenergic receptor- and protein kinase C-mediated regulation. J Mol Cell Cardiol 32:1013–1023

    Article  PubMed  CAS  Google Scholar 

  • Haworth RS, Cuello F, Herron TJ, Franzen G, Kentish JC, Gautel M, Avkiran M (2004) Protein kinase D is a novel mediator of cardiac troponin I phosphorylation and regulates myofilament function. Circ Res 95:1091–1099

    Article  PubMed  CAS  Google Scholar 

  • Haworth RS, Roberts NA, Cuello F, Avkiran M (2007) Regulation of protein kinase D activity in adult myocardium: novel counter-regulatory roles for protein kinase Cε and protein kinase A. J Mol Cell Cardiol 43:686–695

    Article  PubMed  CAS  Google Scholar 

  • Haworth RS, Cuello F, Avkiran M (2011) Regulation by phosphodiesterase isoforms of protein kinase A-mediated attenuation of myocardial protein kinase D activation. Basic Res Cardiol 106:51–63

    Article  PubMed  CAS  Google Scholar 

  • Herron TJ, Korte FS, McDonald KS (2001) Power output is increased after phosphorylation of myofibrillar proteins in rat skinned cardiac myocytes. Circ Res 89:1184–1190

    Article  PubMed  CAS  Google Scholar 

  • Itoh S, Ding B, Bains CP, Wang N, Takeishi Y, Jalili T, King GL, Walsh RA, Yan C, Abe J (2005) Role of p90 ribosomal S6 kinase (p90RSK) in reactive oxygen species and protein kinase C β (PKC-β)-mediated cardiac troponin I phosphorylation. J Biol Chem 280:24135–24142

    Article  PubMed  CAS  Google Scholar 

  • Jacques AM, Copeland O, Messer AE, Gallon CE, King K, McKenna WJ, Tsang VT, Marston SB (2008) Myosin binding protein C phosphorylation in normal, hypertrophic and failing human heart muscle. J Mol Cell Cardiol 45:209–216

    Article  PubMed  CAS  Google Scholar 

  • Jacquet S, Yin X, Sicard P, Clark J, Kanaganayagam GS, Mayr M, Marber MS (2009) Identification of cardiac myosin-binding protein C as a candidate biomarker of myocardial infarction by proteomics analysis. Mol Cell Proteomics 8:2687–2699

    Article  PubMed  CAS  Google Scholar 

  • James J, Robbins J (2011) Signaling and myosin-binding protein C. J Biol Chem 286:9913–9919

    Article  PubMed  CAS  Google Scholar 

  • Jensen BC, Swigart PM, De MT, Hoopes C, Simpson PC (2009) α1-Adrenergic receptor subtypes in nonfailing and failing human myocardium. Circ Heart Fail 2:654–663

    Article  PubMed  CAS  Google Scholar 

  • Jensen BC, O’Connell TD, Simpson PC (2011) α1-Adrenergic receptors: targets for agonist drugs to treat heart failure. J Mol Cell Cardiol 51:518–528

    Article  PubMed  CAS  Google Scholar 

  • Jia W, Shaffer JF, Harris SP, Leary JA (2010) Identification of novel protein kinase A phosphorylation sites in the M-domain of human and murine cardiac myosin binding protein-C using mass spectrometry analysis. J Proteome Res 9:1843–1853

    Article  PubMed  CAS  Google Scholar 

  • Kooij V, Boontje N, Zaremba R, Jaquet K, dos Remedios C, Stienen GJ, van der Velden J (2010) Protein kinase C α and ε phosphorylation of troponin and myosin binding protein C reduce Ca2+ sensitivity in human myocardium. Basic Res Cardiol 105:289–300

    Article  PubMed  CAS  Google Scholar 

  • Layland J, Kentish JC (2000) Effects of α1- or β-adrenoceptor stimulation on work-loop and isometric contractions of isolated rat cardiac trabeculae. J Physiol 524 Pt 1:205–219

    Article  PubMed  CAS  Google Scholar 

  • Layland J, Solaro RJ, Shah AM (2005) Regulation of cardiac contractile function by troponin I phosphorylation. Cardiovasc Res 66:12–21

    Article  PubMed  CAS  Google Scholar 

  • Maekawa N, Abe J, Shishido T, Itoh S, Ding B, Sharma VK, Sheu SS, Blaxall BC, Berk BC (2006) Inhibiting p90 ribosomal S6 kinase prevents Na+–H+ exchanger-mediated cardiac ischemia-reperfusion injury. Circulation 113:2516–2523

    Article  PubMed  CAS  Google Scholar 

  • McClellan G, Kulikovskaya I, Winegrad S (2001) Changes in cardiac contractility related to calcium-mediated changes in phosphorylation of myosin-binding protein C. Biophys J 81:1083–1092

    Article  PubMed  CAS  Google Scholar 

  • Messer AE, Jacques AM, Marston SB (2007) Troponin phosphorylation and regulatory function in human heart muscle: dephosphorylation of Ser23/24 on troponin I could account for the contractile defect in end-stage heart failure. J Mol Cell Cardiol 42:247–259

    Article  PubMed  CAS  Google Scholar 

  • Neumann J, Eschenhagen T, Jones LR, Linck B, Schmitz W, Scholz H, Zimmermann N (1997) Increased expression of cardiac phosphatases in patients with end-stage heart failure. J Mol Cell Cardiol 29:265–272

    Article  PubMed  CAS  Google Scholar 

  • Newton AC (2010) Protein kinase C: poised to signal. Am J Physiol Endocrinol Metab 298:E395–E402

    Article  PubMed  CAS  Google Scholar 

  • O’Connell TD, Swigart PM, Rodrigo MC, Ishizaka S, Joho S, Turnbull L, Tecott LH, Baker AJ, Foster E, Grossman W, Simpson PC (2006) α1-adrenergic receptors prevent a maladaptive cardiac response to pressure overload. J Clin Invest 116:1005–1015

    Article  PubMed  Google Scholar 

  • Pi Y, Zhang D, Kemnitz KR, Wang H, Walker JW (2003) Protein kinase C and A sites on troponin I regulate myofilament Ca2+ sensitivity and ATPase activity in the mouse myocardium. J Physiol 552:845–857

    Article  PubMed  CAS  Google Scholar 

  • Pyle WG, Chen Y, Hofmann PA (2003) Cardioprotection through a PKC-dependent decrease in myofilament ATPase. Am J Physiol Heart Circ Physiol 285:H1220–H1228

    PubMed  CAS  Google Scholar 

  • Robertson SP, Johnson JD, Holroyde MJ, Kranias EG, Potter JD, Solaro RJ (1982) The effect of troponin I phosphorylation on the Ca2+-binding properties of the Ca2+-regulatory site of bovine cardiac troponin. J Biol Chem 257:260–263

    PubMed  CAS  Google Scholar 

  • Sadayappan S, Gulick J, Osinska H, Martin LA, Hahn HS, Dorn GW, Klevitsky R, Seidman CE, Seidman JG, Robbins J (2005) Cardiac myosin-binding protein-C phosphorylation and cardiac function. Circ Res 97:1156–1163

    Article  PubMed  CAS  Google Scholar 

  • Sadayappan S, Osinska H, Klevitsky R, Lorenz JN, Sargent M, Molkentin JD, Seidman CE, Seidman JG, Robbins J (2006) Cardiac myosin binding protein C phosphorylation is cardioprotective. Proc Natl Acad Sci USA 103:16918–16923

    Article  PubMed  CAS  Google Scholar 

  • Sadayappan S, Gulick J, Klevitsky R, Lorenz JN, Sargent M, Molkentin JD, Robbins J (2009) Cardiac myosin binding protein-C phosphorylation in a β-myosin heavy chain background. Circulation 119:1253–1262

    Article  PubMed  CAS  Google Scholar 

  • Sadayappan S, Gulick J, Osinska H, Barefield D, Cuello F, Avkiran M, Lasko VM, Lorenz JN, Maillet M, Martin JL, Brown JH, Bers DM, Molkentin JD, James J, Robbins J (2011) A critical function for Ser-282 in cardiac myosin binding protein-C phosphorylation and cardiac function. Circ Res 109:141–150

    Article  PubMed  CAS  Google Scholar 

  • Schlender KK, Bean LJ (1991) Phosphorylation of chicken cardiac C-protein by calcium/calmodulin-dependent protein kinase II. J Biol Chem 266:2811–2817

    PubMed  CAS  Google Scholar 

  • Schlossarek S, Mearini G, Carrier L (2011) Cardiac myosin-binding protein C in hypertrophic cardiomyopathy: mechanisms and therapeutic opportunities. J Mol Cell Cardiol 50:613–620

    Article  PubMed  CAS  Google Scholar 

  • Sjaastad I, Schiander I, Sjetnan A, Qvigstad E, Bokenes J, Sandnes D, Osnes JB, Sejersted OM, Skomedal T (2003) Increased contribution of alpha 1- vs beta-adrenoceptor-mediated inotropic response in rats with congestive heart failure. Acta Physiol Scand 177:449–458

    Article  PubMed  CAS  Google Scholar 

  • Skomedal T, Borthne K, Aass H, Geiran O, Osnes JB (1997) Comparison between alpha-1 adrenoceptor-mediated and beta adrenoceptor-mediated inotropic components elicited by norepinephrine in failing human ventricular muscle. J Pharmacol Exp Ther 280:721–729

    PubMed  CAS  Google Scholar 

  • Snabaitis AK, Yokoyama H, Avkiran M (2000) Roles of mitogen-activated protein kinases and protein kinase C in α1A-adrenoceptor-mediated stimulation of the sarcolemmal Na+–H+ exchanger. Circ Res 86:214–220

    PubMed  CAS  Google Scholar 

  • Snabaitis AK, Muntendorf A, Wieland T, Avkiran M (2005) Regulation of the extracellular signal-regulated kinase pathway in adult myocardium: differential roles of Gq/11, Gi and G12/13 proteins in signalling by α1-adrenergic, endothelin-1 and thrombin-sensitive protease-activated receptors. Cell Signal 17:655–664

    Article  PubMed  CAS  Google Scholar 

  • Stelzer JE, Patel JR, Walker JW, Moss RL (2007) Differential roles of cardiac myosin-binding protein C and cardiac troponin I in the myofibrillar force responses to protein kinase A phosphorylation. Circ Res 101:503–511

    Article  PubMed  CAS  Google Scholar 

  • Takahashi E, Abe J, Berk BC (1997) Angiotensin II stimulates p90rsk in vascular smooth muscle cells. A potential Na+–H+ exchanger kinase. Circ Res 81:268–273

    PubMed  CAS  Google Scholar 

  • Takeishi Y, Huang Q, Abe J, Glassman M, Che W, Lee JD, Kawakatsu H, Lawrence EG, Hoit BD, Berk BC, Walsh RA (2001) Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: comparison with acute mechanical stretch. J Mol Cell Cardiol 33:1637–1648

    Article  PubMed  CAS  Google Scholar 

  • Takeishi Y, Huang Q, Abe J, Che W, Lee JD, Kawakatsu H, Hoit BD, Berk BC, Walsh RA (2002) Activation of mitogen-activated protein kinases and p90 ribosomal S6 kinase in failing human hearts with dilated cardiomyopathy. Cardiovasc Res 53:131–137

    Article  PubMed  CAS  Google Scholar 

  • Tong CW, Gaffin RD, Zawieja DC, Muthuchamy M (2004) Roles of phosphorylation of myosin binding protein-C and troponin I in mouse cardiac muscle twitch dynamics. J Physiol 558:927–941

    Article  PubMed  CAS  Google Scholar 

  • Tong CW, Stelzer JE, Greaser ML, Powers PA, Moss RL (2008) Acceleration of crossbridge kinetics by protein kinase A phosphorylation of cardiac myosin binding protein C modulates cardiac function. Circ Res 103:974–982

    Article  PubMed  CAS  Google Scholar 

  • Venema RC, Kuo JF (1993) Protein kinase C-mediated phosphorylation of troponin I and C-protein in isolated myocardial cells is associated with inhibition of myofibrillar actomyosin MgATPase. J Biol Chem 268:2705–2711

    PubMed  CAS  Google Scholar 

  • Weisberg A, Winegrad S (1996) Alteration of myosin cross bridges by phosphorylation of myosin-binding protein C in cardiac muscle. Proc Natl Acad Sci USA 93:8999–9003

    Article  PubMed  CAS  Google Scholar 

  • Wijnker PJ, Boknik P, Gergs U, Muller FU, Neumann J, dos Remedios C, Schmitz W, Sindermann JR, Stienen GJ, van der Velden J, Kirchhefer U (2011) Protein phosphatase 2A affects myofilament contractility in non-failing but not in failing human myocardium. J Muscle Res Cell Motil 32:221–233

    Article  PubMed  CAS  Google Scholar 

  • Xiao L, Zhao Q, Du Y, Yuan C, Solaro RJ, Buttrick PM (2007) PKCε increases phosphorylation of the cardiac myosin binding protein C at serine 302 both in vitro and in vivo. Biochemistry 46:7054–7061

    Article  PubMed  CAS  Google Scholar 

  • Yuan C, Guo Y, Ravi R, Przyklenk K, Shilkofski N, Diez R, Cole RN, Murphy AM (2006) Myosin binding protein C is differentially phosphorylated upon myocardial stunning in canine and rat hearts—evidence for novel phosphorylation sites. Proteomics 6:4176–4186

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors’ work in related areas has been funded by awards from the British Heart Foundation (PG/03/053, FS/03/091, PG/05/043, PG/07/056/23150, PG/08/064/25398) and the Medical Research Council (G0001112, G0001227, G0300052, G0800206).

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  1. Cardiovascular Division, King’s College London British Heart Foundation Centre of Research Excellence, The Rayne Institute, St Thomas’ Hospital, London, SE1 7EH, UK

    Sonya C. Bardswell, Friederike Cuello, Jonathan C. Kentish & Metin Avkiran

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  1. Sonya C. Bardswell
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  2. Friederike Cuello
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Correspondence to Metin Avkiran.

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Bardswell, S.C., Cuello, F., Kentish, J.C. et al. cMyBP-C as a promiscuous substrate: phosphorylation by non-PKA kinases and its potential significance. J Muscle Res Cell Motil 33, 53–60 (2012). https://doi.org/10.1007/s10974-011-9276-3

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