Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

p21-activated kinases in cancer

Nature Reviews Cancer volume 6, pages 459–471 (2006)Cite this article

Key Points

  • p21 activated kinases (Paks) are a family of conserved non-receptor serine/threonine kinases that integrate various signalling pathways that are vital to normal cell survival and function.

  • PAK1 is essential for cell transformation that is induced by various oncogenes, and PAK1 and PAK4 are upregulated and activated in several human tumour types.

  • Paks elicit their biological effects mainly through the activity of interacting proteins or kinase substrates that are involved in multiple cell-regulatory pathways that contribute to cell transformation and tumour-cell invasion.

  • Paks modulate the expression of genes for both survival and metastatic potential through transcriptional modulator substrates and by their association with nuclear chromatin.

  • Demonstration of a role for Paks in tumour development and/or maintenance of invasive phenotypes provides another potential strategy for the development of targeted therapies against Paks and their downstream effectors.

  • Drug-discovery efforts have led to the development of several direct and indirect inhibitors of Paks that could potentially be used as anticancer therapeutics.

Abstract

The pivotal role of kinases in signal transduction and cellular regulation has lent them considerable appeal as pharmacological targets across a broad spectrum of cancers. p21-activated kinases (Paks) are serine/threonine kinases that function as downstream nodes for various oncogenic signalling pathways. Paks are well-known regulators of cytoskeletal remodelling and cell motility, but have recently also been shown to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, which results in tumour formation and cell invasiveness. Alterations in Pak expression have been detected in human tumours, which makes them an attractive new therapeutic target.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Modes of PAK1 regulation in normal and cancer cells.
Figure 2: Downstream signalling effectors of PAK1.

Similar content being viewed by others

References

  1. Sells, M. A. et al. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr. Biol. 7, 202–210 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Sells, M. A., Boyd, J. T. & Chernoff, J. p21-activated kinase 1 (Pak1) regulates cell motility in mammalian fibroblasts. J. Cell Biol. 145, 837–849 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bokoch, G. M. Biology of the p21-activated kinases. Ann. Rev. Biochem. 72, 743–781 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Manser, E., Leung, T., Salihuddin, H., Zhao, Z. S. & Lim, L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature 367, 40–46 (1994). Reports the first identification of a Pak family member.

    Article  CAS  PubMed  Google Scholar 

  5. Bokoch, G. M. Regulation of cell function by Rho family GTPases. Immunol. Res. 21, 139–148 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Bar-Sagi, D. & Hall, A. Ras and Rho GTPases: a family reunion. Cell 103, 227–238 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. King, C. C. et al. p21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). J. Biol. Chem. 275, 41201–41209 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Howe, A. K. & Juliano, R. L. Regulation of anchorage-dependent signal transduction by protein kinase A and p21-activated kinase. Nature Cell Biol. 2, 593–600 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Tsakiridis, T., Taha, C., Grinstein, S. & Klip, A. Insulin activates a p21-activated kinase in muscle cells via phosphatidylinositol 3-kinase. J. Biol. Chem. 271, 19664–19667 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Tang, Y., Zhou, H., Chen, A., Pittman, R. N. & Field, J. The Akt proto-oncogene links Ras to Pak and cell survival signals. J. Biol. Chem. 275, 9106–9109 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Callow, M. G. et al. Requirement for PAK4 in the anchorage-independent growth of human cancer cell lines. J. Biol. Chem. 277, 550–558 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Mahlamaki, E. H. et al. High-resolution genomic and expression profiling reveals 105 putative amplification target genes in pancreatic cancer. Neoplasia 6, 432–439 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Huang, Z., Traugh, J. A. & Bishop, J. M. Negative control of the Myc protein by the stress-responsive kinase Pak2. Mol. Cell. Biol. 24, 1582–1594 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Osada, S., Izawa, M., Koyama, T., Hirai, S. & Ohno, S. A domain containing the Cdc42/Rac interactive binding (CRIB) region of p65PAK inhibits transcriptional activation and cell transformation mediated by the Ras-Rac pathway. FEBS Lett. 404, 227–233 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Tang, Y. et al. Kinase-deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts. Mol. Cell. Biol. 17, 4454–4464 (1997). Provides the first demonstration that Pak family kinases are involved in cell transformation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mira, J. P., Benard, V., Groffen, J., Sanders, L. C. & Knaus, U. G. Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway. Proc. Natl Acad. Sci. USA 97, 185–189 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sachdev, P., Zeng, L. & Wang, L. H. Distinct role of phosphatidylinositol 3-kinase and Rho family GTPases in Vav3-induced cell transformation, cell motility, and morphological changes. J. Biol. Chem. 277, 17638–17648 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Balasenthil, S. et al. p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells. J. Biol. Chem. 279, 1422–1428 (2004). First report of a Pak family protein upregulated in human breast tumors. This paper also provided a mechanistic explanation for the increased cell proliferation that follows PAK1 deregulation.

    Article  CAS  PubMed  Google Scholar 

  19. Fiegen, D. et al. Alternative splicing of Rac1 generates Rac1b, a self-activating GTPase. J. Biol. Chem. 279, 4743–4749 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Schnelzer, A. et al. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19, 3013–3020 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Ahn, S. J. et al. Overexpression of betaPix-a in human breast cancer tissues. Cancer Lett. 193, 99–107 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Tang, Y. et al. A role for Pak protein kinases in Schwann cell transformation. Proc. Natl Acad. Sci. USA 95, 5139–5144 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Xiao, G. H., Beeser, A., Chernoff, J. & Testa, J. R. p21-activated kinase links Rac/Cdc42 signaling to merlin. J. Biol. Chem. 277, 883–886 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Kissil, J. L., Johnson, K. C., Eckman, M. S. & Jacks, T. Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization. J. Biol. Chem. 277, 10394–10399 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Kissil, J. L. et al. Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Mol. Cell 12, 841–849 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Vadlamudi, R. K. et al. Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J. Biol. Chem. 275, 36238–36244 (2000). First demonstration of a direct link between deregulated PAK1 expression and aggressive breast cancer cell phenotypes.

    Article  CAS  PubMed  Google Scholar 

  27. Adam, L., Vadlamudi, R., Mandal, M., Chernoff, J. & Kumar, R. Regulation of microfilament reorganization and invasiveness of breast cancer cells by kinase dead p21-activated kinase-1. J. Biol. Chem. 275, 12041–12050 (2000). First report of kinase-indpendent cytoskeletal regulation by Paks. This paper opened up the possibility that Paks might elicit signalling through protein–protein interaction rather than soley through kinase activity.

    Article  CAS  PubMed  Google Scholar 

  28. Adam, L. et al. Heregulin regulates cytoskeletal reorganization and cell migration through the p21-activated kinase-1 via phosphatidylinositol-3 kinase. J. Biol. Chem. 273, 28238–28246 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Salh, B., Marotta, A., Wagey, R., Sayed, M. & Pelech, S. Dysregulation of phosphatidylinositol 3-kinase and downstream effectors in human breast cancer. Int. J. Cancer 98, 148–154 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Wang, R. A., Mazumdar, A., Vadlamudi, R. K. & Kumar, R. P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-alpha and promotes hyperplasia in mammary epithelium. EMBO J. 21, 5437–5447 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang, R.-A., Zhang, H., Balasenthil, S., Medina, D. & Kumar, R. PAK1 hyperactivation is sufficient for mammary gland tumor formation. Oncogene 12 Dec 2005 (doi: 10.1038/sj.onc.1209309). First report to show that PAK1 hyperactivation is sufficicient to cause mammary-gland tumours in mice.

  32. Rayala, S. K. et al. P21-activated kinase 1 regulation of estrogen receptor-alpha activation involves serine 305 activation linked with serine 118 phosphorylation. Cancer Res. 66, 1694–1701 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Holm, C. et al. Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients. J. Natl Cancer Inst. 98, 671–680 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Lee, S. R. et al. AR and ER interaction with a p21-activated kinase (PAK6). Mol. Endocrinol. 16, 85–99 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Burbelo, P. D., Drechsel, D. & Hall, A. A conserved binding motif defines numerous candidate target proteins for both Cdc42 and Rac GTPases. J. Biol. Chem. 270, 29071–29074 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Bokoch, G. M. et al. Interaction of the Nck adapter protein with p21-activated kinase (PAK1). J. Biol. Chem. 271, 25746–25749 (1996). Demonstrates the importance of Pak protein localization within the cell for both kinase activation and substrate specificity.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao, Z. S., Manser, E., Loo, T. H. & Lim, L. Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly. Mol. Cell. Biol. 20, 6354–6363 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hashimoto, S., Tsubouchi, A., Mazaki, Y. & Sabe, H. Interaction of paxillin with p21-activated Kinase (PAK). Association of paxillin alpha with the kinase-inactive and the Cdc42-activated forms of PAK3. J. Biol. Chem. 276, 6037–6045 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Yu, J. S., Chen, W. J., Ni, M. H., Chan, W. H. & Yang, S. D. Identification of the regulatory autophosphorylation site of autophosphorylation-dependent protein kinase (auto-kinase). Evidence that auto-kinase belongs to a member of the p21-activated kinase family. Biochem. J. 334, 121–131 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zenke, F. T., King, C. C., Bohl, B. P. & Bokoch, G. M. Identification of a central phosphorylation site in p21-activated kinase regulating autoinhibition and kinase activity. J. Biol. Chem. 274, 32565–32573 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Bokoch, G. M. et al. A GTPase-independent mechanism of p21-activated kinase activation. Regulation by sphingosine and other biologically active lipids. J. Biol. Chem. 273, 8137–8144 (1998). This report of GTPase-independent Pak activation linked Pak activity with G-protein and lipid signalling, which expanded our knowledge of the cell regulatory functions of Paks.

    Article  CAS  PubMed  Google Scholar 

  42. King, C. C. et al. Sphingosine is a novel activator of 3-phosphoinositide-dependent kinase 1. J. Biol. Chem. 275, 18108–18113 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Nikolic, M., Chou, M. M., Lu, W., Mayer, B. J. & Tsai, L. H. The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature 395, 194–198 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Rashid, T., Banerjee, M. & Nikolic, M. Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology. J. Biol. Chem. 276, 49043–49052 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Thiel, D. A. et al. Cell cycle-regulated phosphorylation of p21-activated kinase 1. Curr. Biol. 12, 1227–1232 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Banerjee, M., Worth, D., Prowse, D. M. & Nikolic, M. Pak1 phosphorylation on t212 affects microtubules in cells undergoing mitosis. Curr. Biol. 12, 1233–1239 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Cau, J. et al. Regulation of Xenopus p21-activated kinase (X-PAK2) by Cdc42 and maturation-promoting factor controls Xenopus oocyte maturation. J. Biol. Chem. 275, 2367–2375 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Tao, W., Pennica, D., Xu, L., Kalejta, R. F. & Levine, A. J. Wrch-1, a novel member of the Rho gene family that is regulated by Wnt-1. Genes Dev. 15, 1796–1807 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Shutes, A., Berzat, A. C., Cox, A. D. & Der, C. J. Atypical mechanism of regulation of the Wrch-1 Rho family small GTPase. Curr. Biol. 14, 2052–2056 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Dan, I., Watanabe, N. M. & Kusumi, A. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol. 11, 220–230 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Slack-Davis, J. K. et al. PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J. Cell Biol. 162, 281–291 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Eblen, S. T., Slack, J. K., Weber, M. J. & Catling, A. D. Rac-PAK signaling stimulates extracellular signal-regulated kinase (ERK) activation by regulating formation of MEK1-ERK complexes. Mol. Cell. Biol. 22, 6023–6033 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. King, A. J. et al. The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature 396, 180–183 (1998).

    Article  CAS  PubMed  Google Scholar 

  54. Edwards, D. C., Sanders, L. C., Bokoch, G. M. & Gill, G. N. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nature Cell Biol. 1, 253–259 (1999). Showed for the first time that Pak phosphorylation of LIMK inhibits cofilin-dependent F-actin disassembly, which therefore stabilizes the actin cytoskeleton.

    Article  CAS  PubMed  Google Scholar 

  55. Misra, U. K., Deedwania, R. & Pizzo, S. V. Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. J. Biol. Chem. 280, 26278–26286 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Bagheri-Yarmand, R., Mazumdar, A., Sahin, A. A. & Kumar, R. LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system. Int. J. Cancer 118, 2703–2710 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Davila, M., Frost, A. R., Grizzle, W. E. & Chakrabarti, R. LIM kinase 1 is essential for the invasive growth of prostate epithelial cells: implications in prostate cancer. J. Biol. Chem. 278, 36868–36875 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Yoshioka, K., Foletta, V., Bernard, O. & Itoh, K. A role for LIM kinase in cancer invasion. Proc. Natl Acad. Sci. USA 100, 7247–7252 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Vadlamudi, R. K., Li, F., Barnes, C. J., Bagheri-Yarmand, R. & Kumar, R. p41-Arc subunit of human Arp2/3 complex is a p21-activated kinase-1-interacting substrate. EMBO Rep. 5, 154–160 (2004). Reports that PAK1 is a direct activator of actin nucleation and branching through the phosphorylation of p41/Arc, which stimulates assembly of the Arp2/3 complex. These experiments showed positive regulation of the actin cytoskeleton by PAK1 and laid the foundation for ongoing studies into PAK1, p41/Arc and human breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vadlamudi, R. K. et al. Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1. Nature Cell Biol. 4, 681–690 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Desai, A. & Mitchison, T. J. Microtubule polymerization dynamics. Ann. Rev. Cell Devel. Biol. 13, 83–117 (1997).

    Article  CAS  Google Scholar 

  62. Jordan, M. A. & Wilson, L. Microtubules as a target for anticancer drugs. Nature Rev. Cancer. 4, 253–265 (2004).

    Article  CAS  Google Scholar 

  63. Cassimeris, L. The oncoprotein 18/stathmin family of microtubule destabilizers. Curr. Opin. Cell Biol. 14, 18–24 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Marklund, U., Larsson, N., Gradin, H. M., Brattsand, G. & Gullberg, M. Oncoprotein 18 is a phosphorylation-responsive regulator of microtubule dynamics. EMBO J. 15, 5290–5298 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Daub, H., Gevaert, K., Vandekerckhove, J., Sobel, A. & Hall, A. Rac/Cdc42 and p65PAK regulate the microtubule-destabilizing protein stathmin through phosphorylation at serine 16. J. Biol. Chem. 276, 1677–1680 (2001). Provided the first regulatory link between Pak activity and the microtubule cell cytoskeleton.

    Article  CAS  PubMed  Google Scholar 

  66. Wittmann, T., Bokoch, G. M. & Waterman-Storer, C. M. Regulation of microtubule destabilizing activity of Op18/stathmin downstream of Rac1. J. Biol. Chem. 279, 6196–6203 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Vadlamudi, R. K. et al. p21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor B. Mol. Cell. Biol. 25, 3726–3736 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Knaus, U. G., Morris, S., Dong, H. J., Chernoff, J. & Bokoch, G. M. Regulation of human leukocyte p21-activated kinases through G protein-coupled receptors. Science 269, 221–223 (1995).

    Article  CAS  PubMed  Google Scholar 

  69. Ahmed, S. et al. Cryptic Rac-binding and p21(Cdc42Hs/Rac)-activated kinase phosphorylation sites of NADPH oxidase component p67(phox). J. Biol. Chem. 273, 15693–15701 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Martyn, K. D., Kim, M.-J., Quinn, M. T., Dinauer, M. C. & Knaus, U. G. p21-activated kinase (Pak) regulates NADPH oxidase activation in human neutrophils. Blood 106, 3962–3969 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Meng, T. C., Fukada, T. & Tonks, N. K. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol. Cell 9, 387–399 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Shalom-Barak, T. & Knaus, U. G. A p21-activated kinase-controlled metabolic switch up-regulates phagocyte NADPH oxidase. J. Biol. Chem. 277, 40659–40665 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Gururaj, A., Barnes, C. J., Vadlamudi, R. K. & Kumar, R. Regulation of phosphoglucomutase 1 phosphorylation and activity by a signaling kinase. Oncogene 23, 8118–8127 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Schurmann, A. et al. p21-activated kinase 1 phosphorylates the death agonist bad and protects cells from apoptosis. Mol. Cell. Biol. 20, 453–461 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jakobi, R., Moertl, E. & Koeppel, M. A. p21-activated protein kinase γ-PAK suppresses programmed cell death of BALB3T3 fibroblasts. J. Biol. Chem. 276, 16624–16634 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Gnesutta, N., Qu, J. & Minden, A. The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis. J. Biol. Chem. 276, 14414–14419 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Cotteret, S., Jaffer, Z. M., Beeser, A. & Chernoff, J. p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Mol. Cell. Biol. 23, 5526–5539 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Vadlamudi, R. K. et al. Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes cancerous phenotypes. Cancer Cell 5, 575–585 (2004). Provided direct evidence that PAK1 phosphorylation of the motor complex protein subunit DLC1 regulated intracellular transport, gene activation, cancer cell susceptibility to apoptosis and progression of cancer cell phenotypes. Ongoing studies are investigating a causal link between PAK1–DLC1 and breast cancer progression.

    Article  CAS  PubMed  Google Scholar 

  79. Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Puthalakath, H., Huang, D. C., O'Reilly, L. A., King, S. M. & Strasser, A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell 3, 287–296 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Mazumdar, A. & Kumar, R. Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells. FEBS Lett. 535, 6–10 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Frost, J. A. et al. Stimulation of NFκB activity by multiple signaling pathways requires PAK1. J. Biol. Chem. 275, 19693–19699 (2000). Highlights the importance of Paks in cell survival signalling.

    Article  CAS  PubMed  Google Scholar 

  83. Foryst-Ludwig, A. & Naumann, M. p21-activated kinase 1 activates the nuclear factor κB (NF-κB)-inducing kinase-Ikappa B kinases NF-κB pathway and proinflammatory cytokines in Helicobacter pylori infection. J. Biol. Chem. 275, 39779–39785 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Rudel, T. & Bokoch, G. M. Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science 276, 1571–1574 (1997). Showed that PAK2 could be activated by proteolytic cleavage and reported a pro-apoptotic rather than anti-apoptotic function for PAK2. These data increased the biological significance of Pak family kinases in apoptotsis regulation and hinted at the complexity of these interactions.

    Article  CAS  PubMed  Google Scholar 

  85. Walter, B. N. et al. Cleavage and activation of p21-activated protein kinase γ-PAK by CPP32 (caspase 3). Effects of autophosphorylation on activity. J. Biol. Chem. 273, 28733–28739 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Lee, N. et al. Activation of hPAK65 by caspase cleavage induces some of the morphological and biochemical changes of apoptosis. Proc. Natl Acad. Sci. USA 94, 13642–13647 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chan, W. H., Yu, J. S. & Yang, S. D. PAK2 is cleaved and activated during hyperosmotic shock-induced apoptosis via a caspase-dependent mechanism: evidence for the involvement of oxidative stress. J. Cell. Physiol. 178, 397–408 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Rudel, T., Zenke, F. T., Chuang, T. H. & Bokoch, G. M. p21-activated kinase (PAK) is required for Fas-induced JNK activation in Jurkat cells. J. Immunol. 160, 7–11 (1998).

    CAS  PubMed  Google Scholar 

  89. Tang, T. K. et al. Proteolytic cleavage and activation of PAK2 during UV irradiation-induced apoptosis in A431 cells. J. Cell. Biochem. 70, 442–454 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Jakobi, R., McCarthy, C. C., Koeppel, M. A. & Stringer, D. K. Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation. J. Biol. Chem. 278, 38675–38685 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Come, C., Arnoux, V., Bibeau, F. & Savagner, P. Roles of the transcription factors snail and slug during mammary morphogenesis and breast carcinoma progression. J. Mammary. Gland. Biol. Neoplasia. 9, 183–193 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Yang, Z. et al. Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. Cancer Res. 65, 3179–3184 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Barnes, C. J. et al. Functional inactivation of a transcriptional corepressor by a signaling kinase. Nature Struct. Biol. 10, 622–628 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Grooteclaes, M. L. & Frisch, S. M. Evidence for a function of CtBP in epithelial gene regulation and anoikis. Oncogene 19, 3823–3828 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Qyang, Y. et al. The p21-activated kinase, Shk1, is required for proper regulation of microtubule dynamics in the fission yeast, Schizosaccharomyces pombe. Mol. Microbiol. 44, 325–334 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Wang, R. A. et al. Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands. J. Cell Biol. 161, 583–592 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Michalides, R. et al. Tamoxifen resistance by a conformational arrest of the estrogen receptor alpha after PKA activation in breast cancer. Cancer Cell 5, 597–605 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Kiosses, W. B. et al. A dominant-negative p65 PAK peptide inhibits angiogenesis. Circ. Res. 90, 697–702 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. He, H. et al. The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation. Cancer Biol. Ther. 3, 96–101 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. He, H. et al. Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation. Cancer J. 7, 191–202 (2001).

    CAS  PubMed  Google Scholar 

  101. Hirokawa, Y. et al. Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). Cancer Lett. (2006).

  102. Huang, Q., Shen, H. M. & Ong, C. N. Emodin inhibits tumor cell migration through suppression of the phosphatidylinositol 3-kinase-Cdc42/Rac1 pathway. Cell Mol. Life Sci. 62, 1167–1175 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Hirokawa, Y., Arnold, M., Nakajima, H., Zalcberg, J. & Maruta, H. Signal therapy of breast cancers by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance. Cancer Biol. Ther. 4, 956–960 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Hirokawa, Y. et al. Signal therapy of NF1-deficient tumor xenograft in mice by the anti-PAK1 drug FK228. Cancer Biol. Ther. 4, 379–381 (2005).

    CAS  PubMed  Google Scholar 

  105. Hirokawa, Y. et al. A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor. Cancer J. 10, 20–26 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Lei, M. et al. Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell 102, 387–397 (2000). This paper together with reference 46 provided important structural information that explainined the mechanism of Pak autoinhibition, activation through interaction with GTPases and three dimensional localization of crucial phosphorylation sites. This information will prove crucial to the rational design of direct small-molecule inhibitors of Pak family kinases.

    Article  CAS  PubMed  Google Scholar 

  107. Morreale, A. et al. Structure of Cdc42 bound to the GTPase binding domain of PAK. Nature Struct. Biol. 7, 384–388 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Li, F. et al. p21-activated kinase 1 interacts with and phosphorylates histone H3 in breast cancer cells. EMBO Rep. 3, 767–773 (2002). Provided evidence of Pak family cell-cycle regulatory functions and linked PAK1 activity with the regulatory steps of mitosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Singh, R. R., Song, C., Yang, Z. & Kumar, R. Nuclear localization and chromatin targets of p21-activated kinase 1. J. Biol. Chem. 280, 18130–18137 (2005). Reports the first demonstration of direct association of PAK1 with nuclear chromatin, and shows both positive and negative transcriptional regulation through PAK1–chromatin association.

    Article  CAS  PubMed  Google Scholar 

  110. Cheung, P., Allis, C. D. & Sassone-Corsi, P. Signaling to chromatin through histone modifications. Cell 103, 263–271 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Nowak, S. J. & Corces, V. G. Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation. Trends Genet. 20, 214–220 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Ke, Y. W., Dou, Z., Zhang, J. & Yao, X. B. Function and regulation of Aurora/Ipl1p kinase family in cell division. Cell Res. 13, 69–81 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Keen, N. & Taylor, S. Aurora-kinase inhibitors as anticancer agents. Nature Rev. Cancer 4, 927–936 (2004).

    Article  CAS  Google Scholar 

  114. Walter, A. O., Seghezzi, W., Korver, W., Sheung, J. & Lees, E. The mitotic serine/threonine kinase Aurora2/AIK is regulated by phosphorylation and degradation. Oncogene 19, 4906–4916 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Chen, S. H. & Tang, T. K. Mutational analysis of the phosphorylation sites of the Aie1 (Aurora-C) kinase in vitro. DNA Cell Biol. 21, 41–46 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Zhao, Z. S., Lim, J. P., Ng, Y. W., Lim, L. & Manser, E. The GIT-associated kinase PAK targets to the centrosome and regulates Aurora-A. Mol. Cell 20, 237–249 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Carter, J. H. et al. Pak-1 expression increases with progression of colorectal carcinomas to metastasis. Clin. Cancer Res. 10, 3448–3456 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Schraml, P. et al. Combined array comparative genomic hybridization and tissue microarray analysis suggest PAK1 at 11q13. 5-q14 as a critical oncogene target in ovarian carcinoma. Am. J. Pathol. 163, 985–992 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Mao, X. et al. Amplification and overexpression of JUNB is associated with primary cutaneous T-cell lymphomas. Blood 101, 1513–1519 (2003).

    Article  CAS  PubMed  Google Scholar 

  120. Xia, C. et al. Regulation of the p21-activated kinase (PAK) by a human Gbeta-like WD-repeat protein, hPIP1. Proc. Natl Acad. Sci. USA 98, 6174–6179 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Alahari, S. K., Reddig, P. J. & Juliano, R. L. The integrin-binding protein Nischarin regulates cell migration by inhibiting PAK. EMBO J. 23, 2777–2788 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Chen, S. et al. The C-terminal kinase domain of the p34cdc2-related PITSLRE protein kinase (p110C) associates with p21-activated kinase 1 and inhibits its activity during anoikis. J. Biol. Chem. 278, 20029–20036 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Koh, C. G., Tan, E. J., Manser, E. & Lim, L. The p21-activated kinase PAK is negatively regulated by POPX1 and POPX2, a pair of serine/threonine phosphatases of the PP2C family. Curr. Biol. 12, 317–321 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Talukder, A. H., Meng, Q. & Kumar, R. CRIPak, a novel endogenous Pak1 inhibitor. Oncogene 25, 1311–1319 (2006).

    Article  CAS  PubMed  Google Scholar 

  125. Zhao, Z. S. et al. A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1. Mol. Cell. Biol. 18, 2153–2163 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Nheu, T. V. et al. The K252a derivatives, inhibitors for the PAK/MLK kinase family selectively block the growth of RAS transformants. Cancer J. 8, 328–336 (2002).

    Article  PubMed  Google Scholar 

  127. Durany, N. et al. Phosphoglycerate mutase, 2, 3-bisphosphoglycerate phosphatase, creatine kinase and enolase activity and isoenzymes in breast carcinoma. Br. J. Cancer 82, 20–27 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Durany, N., Joseph, J., Cruz-Sanchez, F. F. & Carreras, J. Phosphoglycerate mutase, 2, 3-bisphosphoglycerate phosphatase and creatine kinase activity and isoenzymes in human brain tumours. Br. J. Cancer 76, 1139–1149 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Durany, N., Joseph, J., Campo, E., Molina, R. & Carreras, J. Phosphoglycerate mutase, 2, 3-bisphosphoglycerate phosphatase and enolase activity and isoenzymes in lung, colon and liver carcinomas. Br. J. Cancer 75, 969–977 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Narayanan, N. K., Narayanan, B. A. & Nixon, D. W. Resveratrol-induced cell growth inhibition and apoptosis is associated with modulation of phosphoglycerate mutase B in human prostate cancer cells: two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry evaluation. Cancer Detect. Prev. 28, 443–452 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Mazurek, S., Grimm, H., Wilker, S., Leib, S. & Eigenbrodt, E. Metabolic characteristics of different malignant cancer cell lines. Anticancer Res. 18, 3275–3282 (1998).

    CAS  PubMed  Google Scholar 

  132. Gu, Y., Souza, R. F., Wu, R. F., Xu, Y. C. & Terada, L. S. Induction of colonic epithelial cell apoptosis by p47-dependent oxidants. FEBS Lett. 540, 195–200 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. Seru, R. et al. HaRas activates the NADPH oxidase complex in human neuroblastoma cells via extracellular signal-regulated kinase 1/2 pathway. J. Neurochem. 91, 613–622 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Brar, S. S. et al. An NAD(P)H oxidase regulates growth and transcription in melanoma cells. Am. J. Physiol., Cell Physiol. 282, C1212–C1224 (2002).

    Article  CAS  Google Scholar 

  135. Aggarwal, B. B. & Takada, Y. Pro-apototic and anti-apoptotic effects of tumor necrosis factor in tumor cells. Role of nuclear transcription factor NF-κB. Cancer Treat. Res. 126, 103–127 (2005).

    Article  PubMed  Google Scholar 

  136. Karin, M. & Greten, F. R. NF-κB: linking inflammation and immunity to cancer development and progression. Nature Rev. Immunol. 5, 749–759 (2005).

    Article  CAS  Google Scholar 

  137. Hsieh, T. C., Wijeratne, E. K., Liang, J. Y., Gunatilaka, A. L. & Wu, J. M. Differential control of growth, cell cycle progression, and expression of NF-κB in human breast cancer cells MCF-7, MCF-10A, and MDA-MB-231 by ponicidin and oridonin, diterpenoids from the chinese herb Rabdosia rubescens. Biochem. Biophys. Res. Commun. 337, 224–231 (2005).

    Article  CAS  PubMed  Google Scholar 

  138. Feinman, R., Siegel, D. S. & Berenson, J. Regulation of NF-κB in multiple myeloma: therapeutic implications. Clin. Adv. Hematol. Oncol. 2, 162–166 (2004).

    PubMed  Google Scholar 

  139. Emi, M., Kim, R., Tanabe, K., Uchida, Y. & Toge, T. Targeted therapy against Bcl-2-related proteins in breast cancer cells. Breast Cancer Res. 7, R940–R952 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Willis, S. N. & Adams, J. M. Life in the balance: how BH3-only proteins induce apoptosis. Curr. Opin. Cell Biol. 17, 617–625 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kaneda, A., Kaminishi, M., Sugimura, T. & Ushijima, T. Decreased expression of the seven ARP2/3 complex genes in human gastric cancers. Cancer Lett. 212, 203–210 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Flanagan, L. A. et al. Filamin A, the Arp2/3 complex, and the morphology and function of cortical actin filaments in human melanoma cells. J. Cell Biol. 155, 511–517 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Nishio, K. et al. Oncoprotein 18 overexpression increases the sensitivity to vindesine in the human lung carcinoma cells. Cancer. 91, 1494–1499 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Brattsand, G. Correlation of oncoprotein 18/stathmin expression in human breast cancer with established prognostic factors. Br. J. Cancer 83, 311–318 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Alaiya, A. A. et al. Phenotypic analysis of ovarian carcinoma: polypeptide expression in benign, borderline and malignant tumors. Int. J. Cancer 73, 678–683 (1997).

    Article  CAS  PubMed  Google Scholar 

  146. Roos, G., Brattsand, G., Landberg, G., Marklund, U. & Gullberg, M. Expression of oncoprotein 18 in human leukemias and lymphomas. Leukemia. 7, 1538–1546 (1993).

    CAS  PubMed  Google Scholar 

  147. Escobar, M. A., Hoelz, D. J., Sandoval, J. A., Hickey, R. J., Grosfeld, J. L. & Malkas, L. H. Profiling of nuclear extract proteins from human neuroblastoma cell lines: the search for fingerprints. J. Ped. Surg. 40, 349–358 (2005).

    Article  Google Scholar 

  148. Friedrich, B., Gronberg, H., Landstrom, M., Gullberg, M. & Bergh, A. Differentiation-stage specific expression of oncoprotein 18 in human and rat prostatic adenocarcinoma. Prostate 27, 102–109 (1995).

    Article  CAS  PubMed  Google Scholar 

  149. Hoelzinger, D. B. et al. Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets. Neoplasia 7, 7–16 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Singh, S. et al. Overexpression of vimentin: role in the invasive phenotype in an androgen-independent model of prostate cancer. Cancer Res. 63, 2306–2311 (2003).

    CAS  PubMed  Google Scholar 

  151. Hendrix, M. J., Seftor, E. A., Chu, Y. W., Trevor, K. T. & Seftor, R. E. Role of intermediate filaments in migration, invasion and metastasis. Cancer Metast. Rev. 15, 507–525 (1996).

    Article  CAS  Google Scholar 

  152. Vadlamudi, R. K. et al. An essential role of Pak1 phosphorylation of SHARP in Notch signaling. Oncogene 24, 4591–4596 (2005).

    Article  CAS  PubMed  Google Scholar 

  153. Chinnadurai, G. CtBP, an unconventional transcriptional corepressor in development and oncogenesis. Mol. Cell 9, 213–224 (2002).

    Article  CAS  PubMed  Google Scholar 

  154. Barrallo-Gimeno, A. & Nieto, M. A. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Devel. 132, 3151–3161 (2005).

    CAS  Google Scholar 

Download references

Acknowledgements

We thank our colleagues for sharing their unpublished observations and we apologize to several of our colleagues for not citing their primary references owing to space limitation. The work in the Kumar laboratory is supported by the US National Institutes of Health (NIH).

Author information

Authors and Affiliations

  1. The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030-4009, Texas, USA

    Rakesh Kumar, Anupama E. Gururaj & Christopher J. Barnes

Authors
  1. Rakesh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anupama E. Gururaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher J. Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rakesh Kumar.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Omim

NF1

NF2

FURTHER INFORMATION

Rakesh Kumar's homepage

Glossary

Filopodia

Thin protusions from a cell that drive directional cell motility.

Lamellipodia

Broad projections at the leading edge of a motile cell that show highly dynamic behaviour that is characterized by rapid extension and retraction.

Hyperplastic nodules

Hyperplastic nodules are formed by the increased growth of normal cells and are classified as precursor lesions to mammary cancer.

Intraductal neoplasia

Non-cancerous growth of the cells lining the internal and external surfaces of the mammary gland. It is an important sign that breast cancer could develop.

Tamoxifen

Tamoxifen is an anti-oestrogen drug that is widely used as adjuvant therapy for oestrogen receptor (ER)-positive breast tumours.

Microtubule-organizing centres

A structure that is found in all plant and animal cells from which microtubules radiate. In the context of animal cells, the microtubule-organizing centre is the centrosome that usually has a pair of centrioles and is found near the nucleus.

Spindle fibres

Clusters of microtubules that grow out from each centrosome with their plus ends growing towards the metaphase plate during mitosis.

Chromosomal-segregation defects

Defects that arise in daughter cells during the process of physical partition of replicated and aligned chromosomes by the bipolar mitotic spindle during mitosis.

Cell aneuploidy

Having one or more extra (or fewer) chromosomes than the normal diploid (2n) set (for example, 2n+1, 2n − 1).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kumar, R., Gururaj, A. & Barnes, C. p21-activated kinases in cancer. Nat Rev Cancer 6, 459–471 (2006). https://doi.org/10.1038/nrc1892

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1892

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing