PKC phosphorylation of titin's PEVK element: A novel and conserved pathway for modulating myocardial stiffness

Circulation Research

Volumn 105, Issue 7, 2009, Pages 631-638

  Hidalgo, Carlos ^a   Hudson, Bryan ^a   Bogomolovas, Julius ^b   Zhu, Yi ^a   Anderson, Brian ^a   Greaser, Marion ^c   Labeit, Siegfried ^b   Granzier, Henk ^a,d  

^a UNIVERSITY OF ARIZONA   (United States)

^b UNIVERSITY OF HEIDELBERG   (Germany)

^c UNIVERSITY OF WISCONSIN MADISON   (United States)

^d UNIVERSITY OF ARIZONA COLLEGE OF MEDICINE   (United States)

Author keywords

Connectin; Diastole; Passive stiffness; Posttranslational modification

Indexed keywords

ALANINE; CONNECTIN; GLUTAMIC ACID; LYSINE; PHOSPHOPROTEIN PHOSPHATASE 1; PROLINE; PROTEIN KINASE C; PROTEIN KINASE C ALPHA; RECOMBINANT PROTEIN; VALINE;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; HEART; HEART LEFT VENTRICLE; HEART MUSCLE; MASS SPECTROMETRY; MOUSE; MUTATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RIGIDITY; SARCOMERE LENGTH; SITE DIRECTED MUTAGENESIS;

AMINO ACID MOTIFS; AMINO ACID SEQUENCE; ANIMALS; ELASTICITY; GLUTAMIC ACID; HEART VENTRICLES; HUMANS; LYSINE; MALE; MICE; MOLECULAR SEQUENCE DATA; MUSCLE PROTEINS; MUSCLE TONUS; MUTAGENESIS, SITE-DIRECTED; MUTATION; MYOCARDIAL CONTRACTION; MYOCARDIUM; PEPTIDE FRAGMENTS; PHOSPHORYLATION; PROLINE; PROTEIN KINASE C-ALPHA; PROTEIN KINASES; PROTEIN PHOSPHATASE 1; PROTEIN PROCESSING, POST-TRANSLATIONAL; RATS; RECOMBINANT PROTEINS; SIGNAL TRANSDUCTION; SWINE; TANDEM MASS SPECTROMETRY; TIME FACTORS; VALINE;

EID: 70349668973     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.109.198465     Document Type: Article

References (22)

1. Solaro RJ. Multiplex kinase signaling modifies cardiac function at the level of sarcomeric proteins. J Biol Chem. 2008;283:26829-26833.
2. Granzier HL, Labeit S. The giant protein titin: a major player in myo-cardial mechanics, signaling, and disease. Circ Res. 2004;94:284-295.
3. Wu Y, Cazorla O, Labeit D, Labeit S, Granzier H. Changes in titin and collagen underlie diastolic stiffness diversity of cardiac muscle. J Mol Cell Cardiol. 2000;32:2151-2162.
4. Yamasaki R, Wu Y, McNabb M, Greaser M, Labeit S, Granzier H. Protein kinase A phosphorylates titin?s cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes. Circ Res. 2002;90: 1181-1188.
5. Kruger M, Kotter S, Grutzner A, Lang P, Andresen C, Redfield MM, Butt E, Dos Remedios CG, Linke WA. Protein kinase G modulates human, myocardial passive stiffness by phosphorylation of the titin springs. Circ Res. 2008;104:87-94.
6. Fukuda N, Wu Y, Nair P, Granzier HL. Phosphorylation of titin modulates passive stiffness of cardiac muscle in a titin isoform-dependent manner. J Gen Physiol. 2005;125:257-271.
7. Borbely A, Falcao-Pires I, van Heerebeek L, Hamdani N, Edes I, Gavina C, Leite-Moreira AF, Bronzwaer JG, Papp Z, van der Velden J, Stienen GJ, Paulus WJ. Hypophosphorylation of the stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res. 2009;104:780-786.
8. Murphy S, Frishman WH. Protein kinase C in cardiac disease and as a potential therapeutic target. Cardiol Rev. 2005;13:3-12.
9. Belin RJ, Sumandea MP, Allen EJ, Schoenfelt K, Wang H, Solaro RJ, de Tombe PP. Augmented protein kinase C-alpha-induced myofilament protein phosphorylation contributes to myofilament dysfunction in experimental congestive heart failure. Circ Res. 2007;101:195-204.
10. Liu Q, Chen X, Macdonnell SM, Kranias EG, Lorenz JN, Leitges M, Houser SR, Molkentin JD. Protein kinase C{alpha}, but not PKC{beta} or PKC{gamma}, regulates contractility and heart failure susceptibility: implications for ruboxistaurin as a novel therapeutic approach. Circ Res. 2009;105:194-200.
11. Watanabe K, Nair P, Labeit D, Kellermayer MS, Greaser M, Labeit S, Granzier H. Molecular mechanics of cardiac titin?s PEVK and N2B spring elements. J Biol Chem. 2002;277:11549-11558.
12. Zhu Y, Bogolomovas J, Labeit S, Granzier H. Single molecule force spectroscopy of cardiac titin?s N2B element-effects of the molecular chaperone alpha B-crystallin with disease-causing mutations. J Biol Chem. 2009;284:13914-13923.
13. Labeit D, Watanabe K, Witt C, Fujita H, Wu Y, Lahmers S, Funck T, Labeit S, Granzier H. Calcium-dependent molecular spring elements in the giant protein titin. Proc Natl Acad Sci USA. 2003;100:13716-13721.
14. Granzier HL, Irving TC. Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophys J. 1995;68:1027-1044.
15. Kellermayer MS, Smith SB, Bustamante C, Granzier HL. Mechanical fatigue in repetitively stretched single molecules of titin. Biophys J. 2001;80:852-863.
16. Granzier HL, Labeit S. Titin and its associated proteins: the third myofilament system of the sarcomere. Adv Protein Chem. 2005;71:89-119.
17. Trombitas K, Freiburg A, Centner T, Labeit S, Granzier H. Molecular dissection of N2B cardiac titin?s extensibility. Biophys J. 1999;77: 3189-3196.
18. Li H, Oberhauser AF, Redick SD, Carrion-Vazquez M, Erickson HP, Fernandez JM. Multiple conformations of PEVK proteins detected by single-molecule techniques. Proc Natl Acad Sci USA. 2001;98: 10682-10686.
19. Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S. The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res. 2001;89:1065-1072.
20. Pi Y, Zhang D, Kemnitz KR, Wang H, Walker JW. Protein kinase C and A sites on troponin I regulate myofilament Ca2 + sensitivity and ATPase activity in the mouse myocardium. J Physiol. 2003;552:845-857.
21. Linke WA, Kulke M, Li H, Fujita-Becker S, Neagoe C, Manstein DJ, Gautel M, Fernandez JM. PEVK domain of titin: an entropic spring with actin-binding properties. J Struct Biol. 137:194-205, 2002.
22. Hambleton M, York A, Sargent MA, Kaiser RA, Lorenz JN, Robbins J, Molkentin JD. Inducible and myocyte-specific inhibition of PKCalpha enhances cardiac contractility and protects against infarction-induced heart failure. Am J Physiol Heart Circ Physiol. 2007;293:H3768-H3771.