Skip to main content
SpringerLink
Log in

PAK1 is a novel cardiac protective signaling molecule

  • Mini-Review
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

We review here the novel cardiac protective effects of the multifunctional enzyme, p21-activated kinase 1 (PAK1), a member of a serine/threonine protein kinase family. Despite the large body of evidence from studies in noncardiac tissue indicating that PAK1 activity is key in the regulation of a number of cellular functions, the role of PAK1 in the heart has only been revealed over the past few years. In this review, we assemble an overview of the recent findings on PAK1 signaling in the heart, particularly its cardiac protective effects. We present a model for PAK1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by protein phosphatase 2A (PP2A) predominates.We discuss the anti-adrenergic and antihypertrophic cardiac protective effects of PAK1, as well as its role in maintaining ventricular Ca2+ homeostasis and electrophysiological stability under physiological, β-adrenergic and hypertrophic stress conditions.

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.

Similar content being viewed by others

References

  1. Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/ threonine protein kinase activated by Cdc42 and Rac1. Nature 1994; 367(6458): 40–46

    Article  CAS  PubMed  Google Scholar 

  2. Manser E, Lim L. Roles of PAK family kinases. Prog Mol Subcell Biol 1999; 22: 115–133

    Article  CAS  PubMed  Google Scholar 

  3. Hofmann C, Shepelev M, Chernoff J. The genetics of Pak. J Cell Sci 2004; 117(19): 4343–4354

    Article  CAS  PubMed  Google Scholar 

  4. Zhao ZS, Manser E. PAK and other Rho-associated kinases—effectors with surprisingly diverse mechanisms of regulation. Biochem J 2005; 386(2): 201–214

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Ke Y, Lei M, Collins TP, Rakovic S, Mattick PAD, Yamasaki M, Brodie MS, Terrar DA, Solaro RJ. Regulation of L-type calcium channel and delayed rectifier potassium channel activity by p21-activated kinase-1 in guinea pig sinoatrial node pacemaker cells. Circ Res 2007; 100(9): 1317–1327

    Article  CAS  PubMed  Google Scholar 

  6. Sheehan KA, Ke Y, Wolska BM, Solaro RJ. Expression of active p21-activated kinase-1 induces Ca2+ flux modification with altered regulatory protein phosphorylation in cardiac myocytes. Am J Physiol Cell Physiol 2009; 296(1): C47–C58

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. DeSantiago J, Bare DJ, Ke Y, Sheehan KA, Solaro RJ, Banach K. Functional integrity of the T-tubular system in cardiomyocytes depends on p21-activated kinase 1. J Mol Cell Cardiol 2013; 60: 121–128

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Wang Y, Tsui H, Ke Y, Shi Y, Li Y, Davies L, Cartwright EJ, Venetucci L, Zhang H, Terrar DA, Huang CLH, Solaro RJ, Wang X, Lei M. Pak1 is required to maintain ventricular Ca2+ homeostasis and electrophysiological stability through SERCA2a regulation in mice. Circ Arrhythm Electrophysiol 2014, 7(5): 938–948

    Article  CAS  PubMed  Google Scholar 

  9. DeSantiago J, Bare DJ, Xiao L, Ke Y, Solaro RJ, Banach K. p21-Activated kinase1 (Pak1) is a negative regulator of NADPH-oxidase 2 in ventricular myocytes. J Mol Cell Cardiol 2014; 67: 77–85

    Article  CAS  PubMed  Google Scholar 

  10. Liu W, Zi M, Naumann R, Ulm S, Jin J, Taglieri DM, Prehar S, Gui J, Tsui H, Xiao RP, Neyses L, Solaro RJ, Ke Y, Cartwright EJ, Lei M, Wang X. Pak1 as a novel therapeutic target for antihypertrophic treatment in the heart. Circulation 2011; 124(24): 2702–2715

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Liu W, Zi M, Tsui H, Chowdhury SK, Zeef L, Meng QJ, Travis M, Prehar S, Berry A, Hanley NA, Neyses L, Xiao RP, Oceandy D, Ke Y, Solaro RJ, Cartwright EJ, Lei M, Wang X. A novel immunomodulator, FTY-720 reverses existing cardiac hypertrophy and fibrosis from pressure overload by targeting NFAT (nuclear factor of activated T-cells) signaling and periostin. Circ Heart Fail 2013; 6(4): 833–844

    Article  Google Scholar 

  12. Taglieri DM, Monasky MM, Knezevic I, Sheehan KA, Lei M, Wang X, Chernoff J, Wolska BM, Ke Y, Solaro RJ. Ablation of p21-activated kinase-1 in mice promotes isoproterenol-induced cardiac hypertrophy in association with activation of Erk1/2 and inhibition of protein phosphatase 2A. J Mol Cell Cardiol 2011; 51(6): 988–996

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74(5): 1124–1136

    Article  CAS  PubMed  Google Scholar 

  14. Heusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 2008; 118(19): 1915–1919

    Article  PubMed  Google Scholar 

  15. Jin ZQ, Zhang J, Huang Y, Hoover HE, Vessey DA, Karliner JS. A sphingosine kinase 1 mutation sensitizes the myocardium to ischemia/reperfusion injury. Cardiovasc Res 2007; 76(1): 41–50

    Article  CAS  PubMed  Google Scholar 

  16. Lecour S, Smith RM, Woodward B, Opie LH, Rochette L, Sack MN. Identification of a novel role for sphingolipid signaling in TNF alpha and ischemic preconditioning mediated cardioprotection. J Mol Cell Cardiol 2002; 34(5): 509–518

    Article  CAS  PubMed  Google Scholar 

  17. Egom EEA, Ke Y, Musa H, Mohamed TMA, Wang T, Cartwright E, Solaro RJ, Lei M. FTY720 prevents ischemia/reperfusion injuryassociated arrhythmias in an ex vivo rat heart model via activation of Pak1/Akt signaling. J Mol Cell Cardiol 2010; 48(2): 406–414

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Hofmann U, Burkard N, Vogt C, Thoma A, Frantz S, Ertl G, Ritter O, Bonz A. Protective effects of sphingosine-1-phosphate receptor agonist treatment after myocardial ischaemia-reperfusion. Cardiovasc Res 2009; 83(2): 285–293

    Article  CAS  PubMed  Google Scholar 

  19. Egom EEA, Mohamed TMA, Mamas MA, Shi Y, Liu W, Chirico D, Stringer SE, Ke Y, Shaheen M, Wang T, Chacko S, Wang X, Solaro RJ, Fath-Ordoubadi F, Cartwright EJ, Lei M. Activation of Pak1/Akt/eNOS signaling following sphingosine-1-phosphate release as part of a mechanism protecting cardiomyocytes against ischemic cell injury. Am J Physiol Heart Circ Physiol 2011; 301(4): H1487–H1495

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Shiojima I, Walsh K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev 2006; 20(24): 3347–3365

    Article  CAS  PubMed  Google Scholar 

  21. Mao K, Kobayashi S, Jaffer ZM, Huang Y, Volden P, Chernoff J, Liang Q. Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes. J Mol Cell Cardiol 2008; 44(2): 429–434

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Monasky MM, Taglieri DM, Patel BG, Chernoff J, Wolska BM, Ke Y, Solaro RJ. p21-activated kinase improves cardiac contractility during ischemia-reperfusion concomitant with changes in troponin-T and myosin light chain 2 phosphorylation. Am J Physiol Heart Circ Physiol 2012; 302(1): H224–H230

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Nelson TJ, Balza R Jr, Xiao Q, Misra RP. SRF-dependent gene expression in isolated cardiomyocytes: regulation of genes involved in cardiac hypertrophy. J Mol Cell Cardiol 2005; 39(3): 479–489

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Yunbo Ke & R. John Solaro

  2. Faculty of Life Science, University of Manchester, Manchester, M13 9NT, UK

    Xin Wang

  3. Department of Cardiothoracic Surgery, John Radcliffe Hospital; Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK

    Xu Yu Jin

  4. Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK

    Ming Lei

Authors
  1. Yunbo Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xu Yu Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. John Solaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ming Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ming Lei.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ke, Y., Wang, X., Jin, X.Y. et al. PAK1 is a novel cardiac protective signaling molecule. Front. Med. 8, 399–403 (2014). https://doi.org/10.1007/s11684-014-0380-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-014-0380-9

Keywords

Search

Navigation