PAK1 is a novel cardiac protective signaling molecule

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.

Keywords

p21-activated kinase 1 (PAK1) / heart

References

[1] Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature1994; 367(6458): 40-46

[2] Manser E, Lim L. Roles of PAK family kinases. Prog Mol Subcell Biol1999; 22: 115-133

[3] Hofmann C, Shepelev M, Chernoff J. The genetics of Pak. J Cell Sci2004; 117(19): 4343-4354

[4] Zhao ZS, Manser E. PAK and other Rho-associated kinases—effectors with surprisingly diverse mechanisms of regulation. Biochem J2005; 386(2): 201-214

[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 Res2007; 100(9): 1317-1327

[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 Physiol2009; 296(1): C47-C58

[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 Cardiol2013; 60: 121-128

[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 Electrophysiol2014<month>Sep</month><day>12</day>[Epub ahead of print]

[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 Cardiol2014; 67: 77-85

[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. Circulation2011; 124(24): 2702-2715

[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 Fail2013; 6(4): 833-844

[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 Cardiol2011; 51(6): 988-996

[13] Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation1986; 74(5): 1124-1136

[14] Heusch G, Boengler K, Schulz R. Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation2008; 118(19): 1915-1919

[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 Res2007; 76(1): 41-50

[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 Cardiol2002; 34(5): 509-518

[17] Egom EEA, Ke Y, Musa H, Mohamed TMA, Wang T, Cartwright E, Solaro RJ, Lei M. FTY720 prevents ischemia/reperfusion injury-associated arrhythmias in an ex vivo rat heart model via activation of Pak1/Akt signaling. J Mol Cell Cardiol2010; 48(2): 406-414

[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 Res2009; 83(2): 285-293

[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 Physiol2011; 301(4): H1487-H1495

[20] Shiojima I, Walsh K. Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev2006; 20(24): 3347-3365

[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 Cardiol2008; 44(2): 429-434

[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 Physiol2012; 302(1): H224-H230

[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 Cardiol2005; 39(3): 479-489

Acknowledgements

The work was supported by the Medical Research Council (G10002647: ML, XW, EJC, JRS, YBK), the British Heart Foundation (PG/12/21/29473: ML, XW) and the National Natural Science Foundation of China (No. 31171085: ML), NIH Grant HL 064035 (JRS), PO1 HL 062426 (JRS). The authors thank Dr. Emma Bolton for her proof checking and suggestions for improving the manuscript.

Compliance with ethics guidelines

Yunbo Ke, Xin Wang, Xu Yu Jin, R. John Solaro, and Ming Lei declare that they have no conflict of interest. This manuscript is a mini-review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg