Skip to main content

Advertisement

SpringerLink
Log in

Key role of ERK1/2 molecular scaffolds in heart pathology

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The ability of cardiomyocytes to detect mechanical and humoral stimuli is critical for adaptation of the myocardium in response to new conditions and for sustaining the increased workload during stress. While certain stimuli mediate a beneficial adaptation to stress conditions, others result in maladaptive remodelling, ultimately leading to heart failure. Specific signalling pathways activating either adaptive or maladaptive cardiac remodelling have been identified. Paradoxically, however, in a number of cases, the transduction pathways involved in such opposing responses engage the same signalling proteins. A notable example is the Raf–MEK1/2–ERK1/2 signalling pathway that can control both adaptive and maladaptive remodelling. ERK1/2 signalling requires a signalosome complex where a scaffold protein drives the assembly of these three kinases into a linear pathway to facilitate their sequential phosphorylation, ultimately targeting specific effector molecules. Interestingly, a number of different Raf–MEK1/2–ERK1/2 scaffold proteins have been identified, and their role in determining the adaptive or maladaptive cardiac remodelling is a promising field of investigation for the development of therapeutic strategies capable of selectively potentiating the adaptive response.

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
Fig. 2

Similar content being viewed by others

References

  1. Selvetella G, Hirsch E, Notte A, Tarone G, Lembo G (2004) Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence. Cardiovasc Res 63(3):373–380. doi:10.1016/j.cardiores.2004.04.031

    Article  PubMed  CAS  Google Scholar 

  2. Frey N, Olson EN (2003) Cardiac hypertrophy: the good, the bad, and the ugly. Annu Rev Physiol 65:45–79. doi:10.1146/annurev.physiol.65.092101.142243

    Article  PubMed  CAS  Google Scholar 

  3. McMullen JR, Jennings GL (2007) Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure. Clin Exp Pharmacol Physiol 34(4):255–262. doi:10.1111/j.1440-1681.2007.04585.x

    Article  PubMed  CAS  Google Scholar 

  4. Sakata Y, Hoit BD, Liggett SB, Walsh RA, Dorn GW 2nd (1998) Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice. Circulation 97(15):1488–1495

    Article  PubMed  CAS  Google Scholar 

  5. Esposito G, Rapacciuolo A, Naga Prasad SV, Takaoka H, Thomas SA, Koch WJ, Rockman HA (2002) Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation 105(1):85–92

    Article  PubMed  CAS  Google Scholar 

  6. Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C, Latronico MV, Napoli C, Sadoshima J, Croce CM, Ross J Jr (2002) Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci USA 99(19):12333–12338. doi:10.1073/pnas.172376399

    Article  PubMed  CAS  Google Scholar 

  7. Shioi T, Kang PM, Douglas PS, Hampe J, Yballe CM, Lawitts J, Cantley LC, Izumo S (2000) The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J 19(11):2537–2548. doi:10.1093/emboj/19.11.2537

    Article  PubMed  CAS  Google Scholar 

  8. Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard MH, Liao R, Rosenzweig A (2002) Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem 277(25):22896–22901. doi:10.1074/jbc.M200347200

    Article  PubMed  CAS  Google Scholar 

  9. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J, Sah R, Cheng HY, Rybin VO, Lembo G, Fratta L, Oliveira-dos-Santos AJ, Benovic JL, Kahn CR, Izumo S, Steinberg SF, Wymann MP, Backx PH, Penninger JM (2002) Regulation of myocardial contractility and cell size by distinct PI3 K-PTEN signaling pathways. Cell 110(6):737–749. doi:S0092867402009698

    Article  PubMed  CAS  Google Scholar 

  10. Rose BA, Force T, Wang Y (2010) Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale. Physiol Rev 90(4):1507–1546. doi:10.1152/physrev.00054.2009

    Article  PubMed  CAS  Google Scholar 

  11. Lorenz K, Schmitt JP, Vidal M, Lohse MJ (2009) Cardiac hypertrophy: targeting Raf/MEK/ERK1/2-signaling. Int J Biochem Cell Biol 41(12):2351–2355. doi:10.1016/j.biocel.2009.08.002

    Article  PubMed  CAS  Google Scholar 

  12. Casar B, Pinto A, Crespo P (2009) ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task. Cell Cycle 8(7):1007–1013. doi:10.4161/cc.8.7.8078

    Article  PubMed  CAS  Google Scholar 

  13. Yamaguchi O, Watanabe T, Nishida K, Kashiwase K, Higuchi Y, Takeda T, Hikoso S, Hirotani S, Asahi M, Taniike M, Nakai A, Tsujimoto I, Matsumura Y, Miyazaki J, Chien KR, Matsuzawa A, Sadamitsu C, Ichijo H, Baccarini M, Hori M, Otsu K (2004) Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J Clin Invest 114(7):937–943. doi:10.1172/JCI20317

    PubMed  CAS  Google Scholar 

  14. Harris IS, Zhang S, Treskov I, Kovacs A, Weinheimer C, Muslin AJ (2004) Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload. Circulation 110(6):718–723. doi:10.1161/01.CIR.0000138190.50127.6A

    Article  PubMed  CAS  Google Scholar 

  15. Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, Hewett TE, Jones SP, Lefer DJ, Peng CF, Kitsis RN, Molkentin JD (2000) The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J 19(23):6341–6350. doi:10.1093/emboj/19.23.6341

    Article  PubMed  CAS  Google Scholar 

  16. Purcell NH, Wilkins BJ, York A, Saba-El-Leil MK, Meloche S, Robbins J, Molkentin JD (2007) Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci USA 104(35):14074–14079. doi:10.1073/pnas.0610906104

    Article  PubMed  CAS  Google Scholar 

  17. Hunter JJ, Tanaka N, Rockman HA, Ross J Jr, Chien KR (1995) Ventricular expression of a MLC-2v-ras fusion gene induces cardiac hypertrophy and selective diastolic dysfunction in transgenic mice. J Biol Chem 270(39):23173–23178

    Article  PubMed  CAS  Google Scholar 

  18. Zheng M, Dilly K, Dos Santos Cruz J, Li M, Gu Y, Ursitti JA, Chen J, Ross J Jr, Chien KR, Lederer JW, Wang Y (2004) Sarcoplasmic reticulum calcium defect in Ras-induced hypertrophic cardiomyopathy heart. Am J Physiol Heart Circ Physiol 286(1):H424–H433. doi:10.1152/ajpheart.00110.2003

    Article  PubMed  CAS  Google Scholar 

  19. Kehat I, Molkentin JD (2010) Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Ann NY Acad Sci 1188:96–102. doi:10.1111/j.1749-6632.2009.05088.x

    Article  PubMed  CAS  Google Scholar 

  20. Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y (2008) The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat 29(8):992–1006. doi:10.1002/humu.20748

    Article  PubMed  CAS  Google Scholar 

  21. Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, Lopez Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, Marino B, Digilio MC, Zampino G, Ackerman MJ, Dallapiccola B, Tartaglia M, Gelb BD (2007) Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 39(8):1007–1012. doi:10.1038/ng2073

    Article  PubMed  CAS  Google Scholar 

  22. Nakamura T, Colbert M, Krenz M, Molkentin JD, Hahn HS, Dorn GW 2nd, Robbins J (2007) Mediating ERK 1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome. J Clin Invest 117(8):2123–2132. doi:10.1172/JCI30756

    Article  PubMed  CAS  Google Scholar 

  23. Bogoyevitch MA, Sugden PH (1996) The role of protein kinases in adaptational growth of the heart. Int J Biochem Cell Biol 28(1):1–12. doi:1357272595001425

    Article  PubMed  CAS  Google Scholar 

  24. Bueno OF, Molkentin JD (2002) Involvement of extracellular signal-regulated kinases 1/2 in cardiac hypertrophy and cell death. Circ Res 91(9):776–781

    Article  PubMed  CAS  Google Scholar 

  25. Dorn GW 2nd, Force T (2005) Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest 115(3):527–537. doi:10.1172/JCI24178

    PubMed  CAS  Google Scholar 

  26. Wu X, Simpson J, Hong JH, Kim KH, Thavarajah NK, Backx PH, Neel BG, Araki T (2011) MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1 (L613 V) mutation. J Clin Invest 121(3):1009–1025. doi:10.1172/JCI44929

    Article  PubMed  CAS  Google Scholar 

  27. Muchir A, Pavlidis P, Decostre V, Herron AJ, Arimura T, Bonne G, Worman HJ (2007) Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. J Clin Invest 117(5):1282–1293. doi:10.1172/JCI29042

    Article  PubMed  CAS  Google Scholar 

  28. Muchir A, Shan J, Bonne G, Lehnart SE, Worman HJ (2009) Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins. Hum Mol Genet 18(2):241–247. doi:10.1093/hmg/ddn343

    Article  PubMed  CAS  Google Scholar 

  29. Wu W, Muchir A, Shan J, Bonne G, Worman HJ (2011) Mitogen-activated protein kinase inhibitors improve heart function and prevent fibrosis in cardiomyopathy caused by mutation in lamin A/C gene. Circulation 123(1):53–61. doi:CIRCULATIONAHA.110.970673

    Article  PubMed  CAS  Google Scholar 

  30. Lorenz K, Schmitt JP, Schmitteckert EM, Lohse MJ (2009) A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy. Nat Med 15(1):75–83. doi:10.1038/nm.1893

    Article  PubMed  CAS  Google Scholar 

  31. Kolch W (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6(11):827–837. doi:nrm1743

    Article  PubMed  CAS  Google Scholar 

  32. Dhanasekaran DN, Kashef K, Lee CM, Xu H, Reddy EP (2007) Scaffold proteins of MAP-kinase modules. Oncogene 26(22):3185–3202. doi:10.1038/sj.onc.1210411

    Article  PubMed  CAS  Google Scholar 

  33. Kelly PA, Rahmani Z (2005) DYRK1A enhances the mitogen-activated protein kinase cascade in PC12 cells by forming a complex with Ras, B-Raf, and MEK1. Mol Biol Cell 16(8):3562–3573. doi:10.1091/mbc.E04-12-1085

    Article  PubMed  CAS  Google Scholar 

  34. Good MC, Zalatan JG, Lim WA (2011) Scaffold proteins: hubs for controlling the flow of cellular information. Science 332(6030):680–686. doi:10.1126/science.1198701

    Article  PubMed  CAS  Google Scholar 

  35. Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308(5721):512–517. doi:10.1126/science.1109237

    Article  PubMed  CAS  Google Scholar 

  36. Tilley DG (2011) G protein-dependent and G protein-independent signaling pathways and their impact on cardiac function. Circ Res 109(2):217–230. doi:10.1161/CIRCRESAHA.110.231225

    Article  PubMed  CAS  Google Scholar 

  37. Vidal M, Wieland T, Lohse MJ, Lorenz K (2012) Beta-adrenergic receptor stimulation causes cardiac hypertrophy via a Gbetagamma/Erk-dependent pathway. Cardiovasc Res. doi:10.1093/cvr/cvs249

    PubMed  Google Scholar 

  38. Esposito G, Prasad SV, Rapacciuolo A, Mao L, Koch WJ, Rockman HA (2001) Cardiac overexpression of a G(q) inhibitor blocks induction of extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase activity in in vivo pressure overload. Circulation 103(10):1453–1458

    Article  PubMed  CAS  Google Scholar 

  39. Belcheva MM, Coscia CJ (2002) Diversity of G protein-coupled receptor signaling pathways to ERK/MAP kinase. Neurosignals 11(1):34–44. doi:10.1159/000057320

    Article  PubMed  CAS  Google Scholar 

  40. Sheikh F, Raskin A, Chu PH, Lange S, Domenighetti AA, Zheng M, Liang X, Zhang T, Yajima T, Gu Y, Dalton ND, Mahata SK, Dorn GW 2nd, Heller-Brown J, Peterson KL, Omens JH, McCulloch AD, Chen J (2008) An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice. J Clin Invest 118(12):3870–3880. doi:10.1172/JCI34472

    Article  PubMed  CAS  Google Scholar 

  41. Patel PA, Tilley DG, Rockman HA (2008) Beta-arrestin-mediated signaling in the heart. Circ J 72(11):1725–1729. doi:JST.JSTAGE/circj/CJ-08-0734

    Article  PubMed  CAS  Google Scholar 

  42. Rajagopal S, Rajagopal K, Lefkowitz RJ (2010) Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 9(5):373–386. doi:10.1038/nrd3024

    Article  PubMed  CAS  Google Scholar 

  43. Noor N, Patel CB, Rockman HA (2011) Beta-arrestin: a signaling molecule and potential therapeutic target for heart failure. J Mol Cell Cardiol 51(4):534–541. doi:10.1016/j.yjmcc.2010.11.005

    Article  PubMed  CAS  Google Scholar 

  44. Cowling BS, Cottle DL, Wilding BR, D’Arcy CE, Mitchell CA, McGrath MJ (2011) Four and a half LIM protein 1 gene mutations cause four distinct human myopathies: a comprehensive review of the clinical, histological and pathological features. Neuromuscul Disord 21(4):237–251. doi:10.1016/j.nmd.2011.01.001

    Article  PubMed  Google Scholar 

  45. Lee SM, Tsui SK, Chan KK, Garcia-Barcelo M, Waye MM, Fung KP, Liew CC, Lee CY (1998) Chromosomal mapping, tissue distribution and cDNA sequence of four-and-a-half LIM domain protein 1 (FHL1). Gene 216(1):163–170. doi:S0378-1119(98)00302-3

    Article  PubMed  CAS  Google Scholar 

  46. Friedrich FW, Wilding BR, Reischmann S, Crocini C, Lang P, Charron P, Muller OJ, McGrath MJ, Vollert I, Hansen A, Linke WA, Hengstenberg C, Bonne G, Morner S, Wichter T, Madeira H, Arbustini E, Eschenhagen T, Mitchell CA, Isnard R, Carrier L (2012) Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. Hum Mol Genet 21(14):3237–3254. doi:10.1093/hmg/dds157

    Article  PubMed  CAS  Google Scholar 

  47. Chu PH, Ruiz-Lozano P, Zhou Q, Cai C, Chen J (2000) Expression patterns of FHL/SLIM family members suggest important functional roles in skeletal muscle and cardiovascular system. Mech Dev 95(1–2):259–265. doi:S0925477300003415

    Article  PubMed  CAS  Google Scholar 

  48. Gaussin V, Tomlinson JE, Depre C, Engelhardt S, Antos CL, Takagi G, Hein L, Topper JN, Liggett SB, Olson EN, Lohse MJ, Vatner SF, Vatner DE (2003) Common genomic response in different mouse models of beta-adrenergic-induced cardiomyopathy. Circulation 108(23):2926–2933. doi:10.1161/01.CIR.0000101922.18151.7B

    Article  PubMed  CAS  Google Scholar 

  49. Hwang DM, Dempsey AA, Wang RX, Rezvani M, Barrans JD, Dai KS, Wang HY, Ma H, Cukerman E, Liu YQ, Gu JR, Zhang JH, Tsui SK, Waye MM, Fung KP, Lee CY, Liew CC (1997) A genome-based resource for molecular cardiovascular medicine: toward a compendium of cardiovascular genes. Circulation 96(12):4146–4203

    Article  PubMed  CAS  Google Scholar 

  50. Hwang DM, Dempsey AA, Lee CY, Liew CC (2000) Identification of differentially expressed genes in cardiac hypertrophy by analysis of expressed sequence tags. Genomics 66(1):1–14. doi:10.1006/geno.2000.6171

    Article  PubMed  CAS  Google Scholar 

  51. Lim DS, Roberts R, Marian AJ (2001) Expression profiling of cardiac genes in human hypertrophic cardiomyopathy: insight into the pathogenesis of phenotypes. J Am Coll Cardiol 38(4):1175–1180. doi:S0735-1097(01)01509-1

    Article  PubMed  CAS  Google Scholar 

  52. Raskin A, Lange S, Banares K, Lyon RC, Zieseniss A, Lee LK, Yamazaki KG, Granzier HL, Gregorio CC, McCulloch AD, Omens JH, Sheikh F (2012) A novel mechanism involving four-and-a-half lim domain protein-1 and extracellular signal-regulated kinase-2 regulates titin phosphorylation and mechanics. J Biol Chem 287(35):29273–29284. doi:10.1074/jbc.M112.372839

    Article  PubMed  CAS  Google Scholar 

  53. Ren JG, Li Z, Sacks DB (2007) IQGAP1 modulates activation of B-Raf. Proc Natl Acad Sci USA 104(25):10465–10469. doi:10.1073/pnas.0611308104

    Article  PubMed  CAS  Google Scholar 

  54. Roy M, Li Z, Sacks DB (2005) IQGAP1 is a scaffold for mitogen-activated protein kinase signaling. Mol Cell Biol 25(18):7940–7952. doi:10.1128/MCB.25.18.7940-7952.2005

    Article  PubMed  CAS  Google Scholar 

  55. Sbroggio M, Carnevale D, Bertero A, Cifelli G, De Blasio E, Mascio G, Hirsch E, Bahou WF, Turco E, Silengo L, Brancaccio M, Lembo G, Tarone G (2011) IQGAP1 regulates ERK1/2 and AKT signalling in the heart and sustains functional remodelling upon pressure overload. Cardiovasc Res 91(3):456–464. doi:10.1093/cvr/cvr103

    Article  PubMed  CAS  Google Scholar 

  56. Chen F, Zhu HH, Zhou LF, Wu SS, Wang J, Chen Z (2010) IQGAP1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation by Akt activation. Exp Mol Med 42(7):477–483. doi:10.3858/emm.2010.42.7.049

    Article  PubMed  CAS  Google Scholar 

  57. Sbroggio M, Bertero A, Velasco S, Fusella F, De Blasio E, Bahou WF, Silengo L, Turco E, Brancaccio M, Tarone G (2011) ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1. J Cell Sci 124(Pt 20):3515–3524. doi:10.1242/jcs.091140

    Article  PubMed  CAS  Google Scholar 

  58. Ferretti R, Sbroggio M, Di Savino A, Fusella F, Bertero A, Michowski W, Tarone G, Brancaccio M (2011) Morgana and Melusin: Two fairies chaperoning signal transduction. Cell Cycle 10(21):3678–3683. doi:18202

    Article  PubMed  CAS  Google Scholar 

  59. Taipale M, Jarosz DF, Lindquist S (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11(7):515–528. doi:10.1038/nrm2918

    Article  PubMed  CAS  Google Scholar 

  60. Morrison DK, Davis RJ (2003) Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol 19:91–118. doi:10.1146/annurev.cellbio.19.111401.091942

    Article  PubMed  CAS  Google Scholar 

  61. Muller J, Ory S, Copeland T, Piwnica-Worms H, Morrison DK (2001) C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Mol Cell 8(5):983–993. doi:S1097-2765(01)00383-5

    Article  PubMed  CAS  Google Scholar 

  62. Matheny SA, Chen C, Kortum RL, Razidlo GL, Lewis RE, White MA (2004) Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 427(6971):256–260. doi:10.1038/nature02237

    Article  PubMed  CAS  Google Scholar 

  63. Cacace AM, Michaud NR, Therrien M, Mathes K, Copeland T, Rubin GM, Morrison DK (1999) Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14–3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression. Mol Cell Biol 19(1):229–240

    PubMed  CAS  Google Scholar 

  64. Kortum RL, Johnson HJ, Costanzo DL, Volle DJ, Razidlo GL, Fusello AM, Shaw AS, Lewis RE (2006) The molecular scaffold kinase suppressor of Ras 1 is a modifier of RasV12-induced and replicative senescence. Mol Cell Biol 26(6):2202–2214. doi:10.1128/MCB.26.6.2202-2214.2006

    Article  PubMed  CAS  Google Scholar 

  65. Kortum RL, Costanzo DL, Haferbier J, Schreiner SJ, Razidlo GL, Wu MH, Volle DJ, Mori T, Sakaue H, Chaika NV, Chaika OV, Lewis RE (2005) The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates adipogenesis. Mol Cell Biol 25(17):7592–7604. doi:10.1128/MCB.25.17.7592-7604.2005

    Article  PubMed  CAS  Google Scholar 

  66. Zhang Y, Li X, Carpinteiro A, Goettel JA, Soddemann M, Gulbins E (2011) Kinase suppressor of Ras-1 protects against pulmonary Pseudomonas aeruginosa infections. Nat Med 17(3):341–346. doi:10.1038/nm.2296

    Article  PubMed  CAS  Google Scholar 

  67. Vomastek T, Schaeffer HJ, Tarcsafalvi A, Smolkin ME, Bissonette EA, Weber MJ (2004) Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists. Proc Natl Acad Sci USA 101(18):6981–6986. doi:10.1073/pnas.0305894101

    Article  PubMed  CAS  Google Scholar 

  68. Ishibe S, Joly D, Liu ZX, Cantley LG (2004) Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. Mol Cell 16(2):257–267. doi:10.1016/j.molcel.2004.10.006

    Article  PubMed  CAS  Google Scholar 

  69. Yin G, Haendeler J, Yan C, Berk BC (2004) GIT1 functions as a scaffold for MEK1-extracellular signal-regulated kinase 1 and 2 activation by angiotensin II and epidermal growth factor. Mol Cell Biol 24(2):875–885

    Article  PubMed  CAS  Google Scholar 

  70. Pang J, Xu X, Getman MR, Shi X, Belmonte SL, Michaloski H, Mohan A, Blaxall BC, Berk BC (2011) G protein coupled receptor kinase 2 interacting protein 1 (GIT1) is a novel regulator of mitochondrial biogenesis in heart. J Mol Cell Cardiol 51(5):769–776. doi:10.1016/j.yjmcc.2011.06.020

    Article  PubMed  CAS  Google Scholar 

  71. Himpel S, Tegge W, Frank R, Leder S, Joost HG, Becker W (2000) Specificity determinants of substrate recognition by the protein kinase DYRK1A. J Biol Chem 275(4):2431–2438

    Article  PubMed  CAS  Google Scholar 

  72. Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, Okamura H, Bolton D, Feske S, Hogan PG, Rao A (2006) A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441(7093):646–650. doi:10.1038/nature04631

    Article  PubMed  CAS  Google Scholar 

  73. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L, Heit JJ, Kim SK, Yamasaki N, Miyakawa T, Francke U, Graef IA, Crabtree GR (2006) NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441(7093):595–600. doi:10.1038/nature04678

    Article  PubMed  CAS  Google Scholar 

  74. Kuhn C, Frank D, Will R, Jaschinski C, Frauen R, Katus HA, Frey N (2009) DYRK1A is a novel negative regulator of cardiomyocyte hypertrophy. J Biol Chem 284(25):17320–17327. doi:10.1074/jbc.M109.006759

    Article  PubMed  CAS  Google Scholar 

  75. da Costa Martins PA, Salic K, Gladka MM, Armand AS, Leptidis S, el Azzouzi H, Hansen A, Coenen-de Roo CJ, Bierhuizen MF, van der Nagel R, van Kuik J, de Weger R, de Bruin A, Condorelli G, Arbones ML, Eschenhagen T, De Windt LJ (2010) MicroRNA-199b targets the nuclear kinase DYRK1A in an auto-amplification loop promoting calcineurin/NFAT signalling. Nat Cell Biol 12(12):1220–1227. doi:10.1038/ncb2126

    Article  PubMed  Google Scholar 

  76. Grebe C, Klingebiel TM, Grau SP, Toischer K, Didie M, Jacobshagen C, Dullin C, Hasenfuss G, Seidler T (2011) Enhanced expression of DYRK1A in cardiomyocytes inhibits acute NFAT activation but does not prevent hypertrophy in vivo. Cardiovasc Res 90(3):521–528. doi:10.1093/cvr/cvr023

    Article  PubMed  CAS  Google Scholar 

  77. Calvo F, Agudo-Ibanez L, Crespo P (2010) The Ras-ERK pathway: understanding site-specific signaling provides hope of new anti-tumor therapies. BioEssays 32(5):412–421. doi:10.1002/bies.200900155

    Article  PubMed  CAS  Google Scholar 

  78. Matallanas D, Crespo P (2010) New druggable targets in the Ras pathway? Curr Opin Mol Ther 12(6):674–683

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We wish to thank R. Srinivasan for manuscript revision. This work was supported by grants from the Regione Piemonte POR F.E.S.R.2007/2013 “DRUIDI: Piattaforme Innovative per le Scienze della Vita” to G.T. and M.B., Telethon GGP12047 to G.T., FIRB RBFR10L0GK to M.S., PRIN 2010J8RYS7 to M.B. and PRIN 2010RNXM9C to G.T.

Conflict of interest

None declared.

Author information

Author notes

  1. Mauro Sbroggiò

    Present address: Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

Authors and Affiliations

  1. Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Center, University of Torino, via Nizza, 52, 10126, Turin, Italy

    Guido Tarone & Mara Brancaccio

Authors
  1. Guido Tarone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mauro Sbroggiò
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mara Brancaccio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guido Tarone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tarone, G., Sbroggiò, M. & Brancaccio, M. Key role of ERK1/2 molecular scaffolds in heart pathology. Cell. Mol. Life Sci. 70, 4047–4054 (2013). https://doi.org/10.1007/s00018-013-1321-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-013-1321-5

Keywords

Search

Navigation