Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Jianman Guo
  • Jeffrey FieldEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101590


Historical Background

PAKs are a family of protein kinases that were first identified in a screen for proteins that interact with the small G proteins Rac1 and Cdc42. Since these have a molecular weight of 21kd, this kinase was named p21-activated kinase (Manser et al. 1994). PAKs are widely conserved and found in yeast as well as in Drosophila and mammals. They are divided into two groups, group I, which consists of PAK1 (α PAK), PAK2 (γ PAK), and PAK3 (β PAK), and group II which consists of PAK4, PAK5, and PAK6 (Rane and Minden 2014). PAK4, which was identified from a PCR screen with degenerate primers based on the PAK2 kinase domain (Abo et al. 1998; Cotteret and Chernoff 2006), is the founding member of group II PAKs. PAK6 was identified as an androgen receptor (AR)-interacting protein in a yeast two-hybrid screen (Yang et al. 2001). The name PAK7 was retired in 2016, since it is no longer considered a separate protein from PAK 5.


This is a preview of subscription content, log in to check access.


  1. Abo A, Qu J, Cammarano J, Dan C, Fritsch A, Baud V, et al. PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia. EMBO J. 1998;17:6527–40. doi:10.1093/emboj/17.22.6527.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Balasenthil S, Sahin AA, Barnes CJ, Wang RA, Pestell RG, Vadlamudi RK, et al. p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells. J Biol Chem. 2004;279:1422–8. doi:10.1074/jbc.M309937200.CrossRefPubMedGoogle Scholar
  3. Banerjee M, Worth D, Prowse DM, Nikolic M. Pak1 phosphorylation on T212 affects microtubules in cells undergoing mitosis. Curr Biol. 2002;12:1233–9.CrossRefPubMedGoogle Scholar
  4. Baskaran Y, Ng YW, Selamat W, Ling FT, Manser E. Group I and II mammalian PAKs have different modes of activation by Cdc42. EMBO Rep. 2012;13:653–9. doi:10.1038/embor.2012.75.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem. 2003;72:743–81. doi:10.1146/annurev.biochem.72.121801.161742.CrossRefPubMedGoogle Scholar
  6. Bokoch GM, Wang Y, Bohl BP, Sells MA, Quilliam LA, Knaus UG. Interaction of the Nck adapter protein with p21-activated kinase (PAK1). J Biol Chem. 1996;271:25746–9.CrossRefPubMedGoogle Scholar
  7. Buchwald G, Hostinova E, Rudolph MG, Kraemer A, Sickmann A, Meyer HE, et al. Conformational switch and role of phosphorylation in PAK activation. Mol Cell Biol. 2001;21:5179–89. doi:10.1128/MCB.21.15.5179-5189.2001.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Callow MG, Clairvoyant F, Zhu S, Schryver B, Whyte DB, Bischoff JR, et al. Requirement for PAK4 in the anchorage-independent growth of human cancer cell lines. J Biol Chem. 2002;277:550–8. doi:10.1074/jbc.M105732200.CrossRefPubMedGoogle Scholar
  9. Carter JH, Douglass LE, Deddens JA, Colligan BM, Bhatt TR, Pemberton JO, et al. Pak-1 expression increases with progression of colorectal carcinomas to metastasis. Clin Cancer Res. 2004;10:3448–56. doi:10.1158/1078-0432.CCR-03-0210.CrossRefPubMedGoogle Scholar
  10. Chauhan SC, Ebeling MC, Maher DM, Koch MD, Watanabe A, Aburatani H, et al. MUC13 mucin augments pancreatic tumorigenesis. Mol Cancer Ther. 2012;11:24–33. doi:10.1158/1535-7163.MCT-11-0598.CrossRefPubMedGoogle Scholar
  11. Chen S, Auletta T, Dovirak O, Hutter C, Kuntz K, El-ftesi S, et al. Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification. Cancer Biol Ther. 2008;7:1793–802.CrossRefPubMedGoogle Scholar
  12. Ching YP, Leong VY, Wong CM, Kung HF. Identification of an autoinhibitory domain of p21-activated protein kinase 5. J Biol Chem. 2003;278:33621–4. doi:10.1074/jbc.C300234200.CrossRefPubMedGoogle Scholar
  13. Chow HY, Jubb AM, Koch JN, Jaffer ZM, Stepanova D, Campbell DA, et al. p21-activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model. Cancer Res. 2012;72:5966–75. doi:10.1158/0008-5472.can-12-2246.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Cotteret S, Chernoff J. Nucleocytoplasmic shuttling of Pak5 regulates its antiapoptotic properties. Mol Cell Biol. 2006;26:3215–30. doi:10.1128/MCB.26.8.3215-3230.2006.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Deacon SW, Beeser A, Fukui JA, Rennefahrt UEE, Myers C, Chernoff J, et al. An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase. Chem Biol. 2008;15:322–31. doi:10.1016/j.chembiol.2008.03.005.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Dummler B, Ohshiro K, Kumar R, Field J. Pak protein kinases and their role in cancer. Cancer Metastasis Rev. 2009;28:51–63. doi:10.1007/s10555-008-9168-1.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Field J, Manser E. The PAKs come of age: celebrating 18 years of discovery. Cell Logist. 2012;2:54–8. doi:10.4161/cl.22084.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Friedland JC, Lakins JN, Kazanietz MG, Chernoff J, Boettiger D, Weaver VM. alpha6beta4 integrin activates Rac-dependent p21-activated kinase 1 to drive NF-kappaB-dependent resistance to apoptosis in 3D mammary acini. J Cell Sci. 2007;120:3700–12. doi:10.1242/jcs.03484.CrossRefPubMedGoogle Scholar
  19. Frost JA, Swantek JL, Stippec S, Yin MJ, Gaynor R, Cobb MH. Stimulation of NFkappa B activity by multiple signaling pathways requires PAK1. J Biol Chem. 2000;275:19693–9. doi:10.1074/jbc.M909860199.CrossRefPubMedGoogle Scholar
  20. Galisteo ML, Chernoff J, Su Y-C, Skolnik EY, Schlessinger J. The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase Pak1. J Biol Chem. 1996;271:20997–1000.CrossRefPubMedGoogle Scholar
  21. Ha BH, Davis MJ, Chen C, Lou HJ, Gao J, Zhang R, et al. Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate. Proc Natl Acad Sci USA. 2012;109:16107–12. doi:10.1073/pnas.1214447109.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hashimoto H, Sudo T, Maruta H, Nishimura R. The direct PAK1 inhibitor, TAT-PAK18, blocks preferentially the growth of human ovarian cancer cell lines in which PAK1 is abnormally activated by autophosphorylation at Thr 423. Drug Discov Ther. 2010;4:1–4.PubMedGoogle Scholar
  23. Higuchi M, Onishi K, Kikuchi C, Gotoh Y. Scaffolding function of PAK in the PDK1-Akt pathway. Nat Cell Biol. 2008;1356–64. doi:10.1038/ncb1795.CrossRefPubMedGoogle Scholar
  24. Hirokawa Y, Tikoo A, Huynh J, Utermark T, Hanemann CO, Giovannini M, et al. A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor. Cancer J. 2004;10:20–6.CrossRefPubMedGoogle Scholar
  25. Jagadeeshan S, Krishnamoorthy YR, Singhal M, Subramanian A, Mavuluri J, Lakshmi A, et al. Transcriptional regulation of fibronectin by p21-activated kinase-1 modulates pancreatic tumorigenesis. Oncogene. 2015;34:455–64. doi:10.1038/onc.2013.576.CrossRefPubMedGoogle Scholar
  26. Jha RK, Strauss CE. 3D structure analysis of PAKs: a clue to the rational design for affinity reagents and blockers. Cell Logist. 2012;2:69–77. doi:10.4161/cl.21883.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Karpov AS, Amiri P, Bellamacina C, Bellance M-H, Breitenstein W, Daniel D, et al. Optimization of a dibenzodiazepine hit to a potent and selective allosteric PAK1 inhibitor. ACS Med Chem Lett. 2015;776–81. doi:10.1021/acsmedchemlett.5b00102.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kelly ML, Chernoff J. Mouse models of PAK function. Cell Logist. 2012;2:84–8. doi:10.4161/cl.21381.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kim EK, Yun SJ, Ha JM, Kim YW, Jin IH, Yun J, et al. Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis. Oncogene. 2011;30:2954–63. doi:10.1038/onc.2011.22.CrossRefPubMedGoogle Scholar
  30. Kimmelman AC, Hezel AF, Aguirre AJ, Zheng H, Paik JH, Ying H, et al. Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc Natl Acad Sci USA. 2008;105:19372–7. doi:10.1073/pnas.0809966105.CrossRefPubMedPubMedCentralGoogle Scholar
  31. King CC, Gardiner MM, Zenke FT, Bohl BP, Newton AC, Hemmings BA, et al. p21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). J Biol Chem. 2000;275:41201–9. doi:10.1074/jbc.M006553200.CrossRefPubMedGoogle Scholar
  32. Kissil JL, Wilker EW, Johnson KC, Eckman MS, Yaffe MB, Jacks T. Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Mol Cell. 2003;12:841–9.CrossRefPubMedGoogle Scholar
  33. Kissil JL, Walmsley MJ, Hanlon L, Haigis KM, Bender Kim CF, Sweet-Cordero A, et al. Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res. 2007;67:8089–94. doi:10.1158/0008-5472.can-07-2300.CrossRefPubMedGoogle Scholar
  34. Lee SH, Jung YS, Chung JY, Oh AY, Lee SJ, Choi DH, et al. Novel tumor suppressive function of Smad4 in serum starvation-induced cell death through PAK1-PUMA pathway. Cell Death Dis. 2011;2:e235. doi:10.1038/cddis.2011.116.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lei M, Lu W, Meng W, Parrini MC, Eck MJ, Mayer BJ, et al. Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell. 2000;102:387–97.CrossRefPubMedGoogle Scholar
  36. Licciulli S, Maksimoska J, Zhou C, Troutman S, Kota S, Liu Q, et al. FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J Biol Chem. 2013;288:29105–14. doi:10.1074/jbc.M113.510933.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Liu Y, Xiao H, Tian Y, Nekrasova T, Hao X, Lee HJ, et al. The pak4 protein kinase plays a key role in cell survival and tumorigenesis in athymic mice. Mol Cancer Res. 2008;6:1215–24. doi:10.1158/1541-7786.MCR-08-0087.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Loo TH, Ng YW, Lim L, Manser E. GIT1 activates p21-activated kinase through a mechanism independent of p21 binding. Mol Cell Biol. 2004;24:3849–59.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Lu W, Katz S, Gupta R, Mayer BJ. Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck. Curr Biol. 1997;7:85–94.CrossRefPubMedGoogle Scholar
  40. Lu Y, Pan ZZ, Devaux Y, Ray P. p21-activated protein kinase 4 (PAK4) interacts with the keratinocyte growth factor receptor and participates in keratinocyte growth factor-mediated inhibition of oxidant-induced cell death. J Biol Chem. 2003;278:10374–80. doi:10.1074/jbc.M205875200.CrossRefPubMedGoogle Scholar
  41. Maksimoska J, Feng L, Harms K, Yi C, Kissil J, Marmorstein R, et al. Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes. J Am Chem Soc. 2008;130:15764–5. doi:10.1021/ja805555a.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature. 1994;367:40–6. doi:10.1038/367040a0.CrossRefPubMedGoogle Scholar
  43. Manser E, Chong C, Zhao ZS, Leung T, Michael G, Hall C, et al. Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family. J Biol Chem. 1995;270:25070–8.CrossRefPubMedGoogle Scholar
  44. Murray BW, Guo C, Piraino J, Westwick JK, Zhang C, Lamerdin J, et al. Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci. 2010;107:9446–51. doi:10.1073/pnas.0911863107.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Ng YW, Raghunathan D, Chan PM, Baskaran Y, Smith DJ, Lee CH, et al. Why an A-loop phospho-mimetic fails to activate PAK1: understanding an inaccessible kinase state by molecular dynamics simulations. Structure. 2010;18:879–90. doi:10.1016/j.str.2010.04.011.CrossRefPubMedGoogle Scholar
  46. Ong CC, Jubb AM, Haverty PM, Zhou W, Tran V, Truong T, et al. Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells. Proc Natl Acad Sci USA. 2011;108:7177–82. doi:10.1073/pnas.1103350108.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Ong CC, Gierke S, Pitt C, Sagolla M, Cheng CK, Zhou W, et al. Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents. Breast Cancer Res. 2015;17:59. doi:10.1186/s13058-015-0564-5.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Pirruccello M, Sondermann H, Pelton JG, Pellicena P, Hoelz A, Chernoff J, et al. A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases. J Mol Biol. 2006;361:312–26. doi:10.1016/j.jmb.2006.06.017.CrossRefPubMedGoogle Scholar
  49. Porchia LM, Guerra M, Wang YC, Zhang Y, Espinosa AV, Shinohara M, et al. 2-Amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phe nyl} Acetamide (OSU-03012), a Celecoxib Derivative, Directly Targets p21-Activated Kinase. Mol Pharmacol. 2007;72:1124–31. doi:10.1124/mol.107.037556.CrossRefPubMedGoogle Scholar
  50. Prudnikova TY, Villamar-Cruz O, Rawat SJ, Cai KQ, Chernoff J. Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells. Oncogene. 2016;35:2178–85. doi:10.1038/onc.2015.278.CrossRefPubMedGoogle Scholar
  51. Radu M, Semenova G, Kosoff R, Chernoff J. PAK signalling during the development and progression of cancer. Nat Rev Cancer. 2014;14:13–25.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Rane CK, Minden A. P21 activated kinases: structure, regulation, and functions. Small GTPases. 2014;5:e28003. doi:10.4161/sgtp.28003.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Rayala SK, Talukder AH, Balasenthil S, Tharakan R, Barnes CJ, Wang RA, et al. P21-activated kinase 1 regulation of estrogen receptor-alpha activation involves serine 305 activation linked with serine 118 phosphorylation. Cancer Res. 2006;66:1694–701. doi:10.1158/0008-5472.CAN-05-2922.CrossRefPubMedGoogle Scholar
  54. Rennefahrt UEE, Deacon SW, Parker SA, Devarajan K, Beeser A, Chernoff J, et al. Specificity profiling of Pak kinases allows identification of novel phosphorylation sites. J Biol Chem. 2007;282:15667–78. doi:10.1074/jbc.M700253200.CrossRefPubMedGoogle Scholar
  55. Rudolph J, Crawford JJ, Hoeflich KP, Wang W. Inhibitors of p21-activated kinases (PAKs). J Med Chem. 2015;58:111–29. doi:10.1021/jm501613q.CrossRefPubMedGoogle Scholar
  56. Rudolph J, Murray LJ, Ndubaku CO, O’Brien T, Blackwood E, Wang W, et al. Chemically diverse group I p21-Activated Kinase (PAK) inhibitors impart acute cardiovascular toxicity with a narrow therapeutic window. J Med Chem. 2016;59:5520–41. doi:10.1021/acs.jmedchem.6b00638.CrossRefPubMedGoogle Scholar
  57. Tabanifar B, Zhao Z, Manser E. PAK5 is auto-activated by a central domain that promotes kinase oligomerization. Biochem J. 2016;473:1777–89. doi:10.1042/BCJ20160132.CrossRefPubMedGoogle Scholar
  58. Tang Y, Chen Z, Ambrose D, Liu J, Gibbs JB, Chernoff J, et al. Kinase-deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts. Mol Cell Biol. 1997;17:4454–64.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Tang Y, Zhou H, Chen A, Pittman RN, Field J. The Akt proto-oncogene links Ras to Pak and cell survival signals. J Biol Chem. 2000;275:9106–9.CrossRefPubMedGoogle Scholar
  60. Teng TS, Lin B, Manser E, Ng DCH, Cao X. Stat3 promotes directional cell migration by regulating Rac1 activity via its activator {beta}PIX. J Cell Sci. 2009;122:4150–9. doi:10.1242/jcs.057109.CrossRefPubMedGoogle Scholar
  61. Thiel DA, Reeder MK, Pfaff A, Coleman TR, Sells MA, Chernoff JA. Cell cycle regulated phosphorylation of p21-activated kinase 1. Curr Biol. 2002;12:1227–32.CrossRefPubMedGoogle Scholar
  62. Timm T, Matenia D, Li XY, Griesshaber B, Mandelkow EM. Signaling from MARK to tau: regulation, cytoskeletal crosstalk, and pathological phosphorylation. Neurodegener Dis. 2006;3:207–17. doi:10.1159/000095258.CrossRefPubMedGoogle Scholar
  63. Wang RA, Mazumdar A, Vadlamudi RK, Kumar R. P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-alpha and promotes hyperplasia in mammary epithelium. EMBO J. 2002;21:5437–47.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Wells CM, Abo A, Ridley AJ. PAK4 is activated via PI3K in HGF-stimulated epithelial cells. J Cell Sci. 2002;115:3947–56.CrossRefPubMedGoogle Scholar
  65. Yang F, Li X, Sharma M, Zarnegar M, Lim B, Sun Z. Androgen receptor specifically interacts with a novel p21-activated kinase, PAK6. J Biol Chem. 2001;276:15345–53. doi:10.1074/jbc.M010311200.CrossRefPubMedGoogle Scholar
  66. Ye DZ, Field J. PAK signaling in cancer. Cell Logist. 2012;2:105–16. doi:10.4161/cl.21882.CrossRefPubMedPubMedCentralGoogle Scholar
  67. Yeo D, Huynh N, Beutler JA, Christophi C, Shulkes A, Baldwin GS, et al. Glaucarubinone and gemcitabine synergistically reduce pancreatic cancer growth via down-regulation of P21-activated kinases. Cancer Lett. 2014;346:264–72. doi:10.1016/j.canlet.2014.01.001.CrossRefPubMedGoogle Scholar
  68. Yi C, Wilker EW, Yaffe MB, Stemmer-Rachamimov A, Kissil JL. Validation of the p21-activated kinases as targets for inhibition in neurofibromatosis Type 2. Cancer Res. 2008;68:7932–7. doi:10.1158/0008-5472.can-08-0866.CrossRefPubMedPubMedCentralGoogle Scholar
  69. Zhao ZS, Manser E. PAK family kinases: physiological roles and regulation. Cell Logist. 2012;2:59–68. doi:10.4161/cl.21912.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Systems Pharmacology and Translational Therapeutics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA