PAK4

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Serine/threonine-protein kinase PAK 4 is an enzyme that in humans is encoded by the PAK4 gene.[1][2][3]

PAK4 is one of six members of the PAK family of serine/threonine kinases which are divided into group I (PAK1, PAK2 and PAK3) and group II (PAK4, PAK6 and PAK5/7).[4][5] PAK4 localizes in sub-cellular domains of the cytoplasm and nucleus.[4][6][7] PAK4 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects directional motility, invasion, metastasis, and growth.[8] Similar to PAK1, PAK4-signaling dependent cellular functions also regulate both physiologic and disease processes such as cancer as PAK4 is overexpressed and/or hyperstimulated in human cancer, at-large.[9][10]

Discovery

PAK4, the founding member of Group II PAK member, was cloned and identified by Minden A. and colleagues in 1998 using a PCR-based strategy from a cDNA library prepared from Jurkett cells.[4]

Gene and spliced variants

The group II PAKs have less coding exons compared with group I PAKs, highlights the potential structural and functional differences between two group of PAKs. The human PAK4 is about 57-kb in length with 13 exons. The PAK4 generates 12 transcripts of which 10 coding transcripts are predicted to code proteins of about 438 to 591 amino acids long, while remaining two transcripts are non-coding in nature. In contrast to human PAK4, murine PAK4 contains four transcripts - two coding for 593 amino acids long polypeptides and two are non-coding RNA transcripts.

Protein domains

The core domains of PAK4 include, a kinase domain in the C-terminal region, a p21-binding domain (PBD), and a newly defined auto-inhibitory domain (AID) [11] or an AID-like pseudosubstrate sequence (PS) domain.[12]

Regulation

PAK4 activity is stimulated by upstream activators and signals, including by HGF,[13] PKD,[14][15] PKA,[16] CDK5RAP3,[17] and SH3RF2.[18]

In addition to other mechanisms, PAK4 functions are mediated though phosphorylation of its effector proteins, including, LIMK1-Thr508,[19] integrin β5-Ser759/Ser762,[20] p120-catenin-Ser288,[21] superior cervical ganglia 10 (SCG10)-Ser50,[22] GEF-H1-Ser810[7][23] β-catenin-Ser675,[6] and Smad2-Ser465.[24]

PAK4 and/or PAK4-dependent signals also modulate the expression of genomic targets, including MT1-MMP[25] and p57Kip2.[26]

Inhibitors

The PAK4 activity and expression has been shown to be inhibited by chemical inhibitors such as PF-3758309,[27] LCH-7749944,[28] glaucarubinone,[29] KY-04031,[30] KY-04045,[31] 1-phenanthryl-tetrahydroisoquinoline derivatives,[32] (-)-β-hydrastine,[33] Inka1,[34] GL-1196,[35] GNE-2861,[36] and microRNAs such as miR-145,[37] miR-433,[38] and miR-126.[39]

Function

PAK proteins, a family of serine/threonine p21-activating kinases, include PAK1, PAK2, PAK3 and PAK4. PAK proteins are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. They serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK4 interacts specifically with the GTP-bound form of Cdc42Hs and weakly activates the JNK family of MAP kinases. PAK4 is a mediator of filopodia formation and may play a role in the reorganization of the actin cytoskeleton. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[3] PAK4 has been shown to be repressed at translational level by miR-24.[40]

PAK4 regulates cellular processes by its scaffolding activity and/or by phosphorylation of effector substrates, which in-turn, set-up a cascades of biochemical events cumulating into a cellular phenotypic response. Examples of PAK4-regulated cellular processes include, dynamic reorganization of actin,[19] and microtubule fibers,[22] anchorage-independent growth,[41] filopodium formation,[4] and cell motility</ref>

  • ITGB5,[42] cell survival[43] embryonic development,[44] supports stem cell-like phenotypes,[45] and gene expression.[6] Modulation of PAK4 signaling has been shown to lead to significant functional implications in a number of disease conditions, exemplified by oncogenesis,[24] cancer cell invasion and metastasis.[22][46]

Interactions

PAK4 has been shown to interact with:

Notes


References

  1. 1.0 1.1 Abo A, Qu J, Cammarano MS, Dan C, Fritsch A, Baud V, Belisle B, Minden A (November 1998). "PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia". The EMBO Journal. 17 (22): 6527–40. doi:10.1093/emboj/17.22.6527. PMC 1171000. PMID 9822598.
  2. Bagrodia S, Cerione RA (September 1999). "Pak to the future". Trends in Cell Biology. 9 (9): 350–5. doi:10.1016/S0962-8924(99)01618-9. PMID 10461188.
  3. 3.0 3.1 "Entrez Gene: PAK4 p21(CDKN1A)-activated kinase 4".
  4. 4.0 4.1 4.2 4.3 Abo A, Qu J, Cammarano MS, Dan C, Fritsch A, Baud V, Belisle B, Minden A (November 1998). "PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia". The EMBO Journal. 17 (22): 6527–40. doi:10.1093/emboj/17.22.6527. PMC 1171000. PMID 9822598.
  5. Vadlamudi RK, Kumar R (December 2003). "P21-activated kinases in human cancer". Cancer Metastasis Reviews. 22 (4): 385–93. doi:10.1023/a:1023729130497. PMID 12884913.
  6. 6.0 6.1 6.2 Li Y, Shao Y, Tong Y, Shen T, Zhang J, Li Y, Gu H, Li F (February 2012). "Nucleo-cytoplasmic shuttling of PAK4 modulates β-catenin intracellular translocation and signaling". Biochimica et Biophysica Acta. 1823 (2): 465–75. doi:10.1016/j.bbamcr.2011.11.013. PMID 22173096.
  7. 7.0 7.1 Callow MG, Zozulya S, Gishizky ML, Jallal B, Smeal T (May 2005). "PAK4 mediates morphological changes through the regulation of GEF-H1". Journal of Cell Science. 118 (Pt 9): 1861–72. doi:10.1242/jcs.02313. PMID 15827085.
  8. Shao YG, Ning K, Li F (January 2016). "Group II p21-activated kinases as therapeutic targets in gastrointestinal cancer". World Journal of Gastroenterology. 22 (3): 1224–35. doi:10.3748/wjg.v22.i3.1224. PMC 4716033. PMID 26811660.
  9. Li X, Liu F, Li F (April 2010). "PAK as a therapeutic target in gastric cancer". Expert Opinion on Therapeutic Targets. 14 (4): 419–33. doi:10.1517/14728221003642019. PMID 20146633.
  10. Kumar R, Li DQ (2016). "PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology". Advances in Cancer Research. 130: 137–209. doi:10.1016/bs.acr.2016.01.002. PMID 27037753.
  11. Baskaran Y, Ng YW, Selamat W, Ling FT, Manser E (June 2012). "Group I and II mammalian PAKs have different modes of activation by Cdc42". EMBO Reports. 13 (7): 653–9. doi:10.1038/embor.2012.75. PMC 3388789. PMID 22653441.
  12. Ha BH, Davis MJ, Chen C, Lou HJ, Gao J, Zhang R, Krauthammer M, Halaban R, Schlessinger J, Turk BE, Boggon TJ (October 2012). "Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate". Proceedings of the National Academy of Sciences of the United States of America. 109 (40): 16107–12. doi:10.1073/pnas.1214447109. PMC 3479536. PMID 22988085.
  13. Wells CM, Abo A, Ridley AJ (October 2002). "PAK4 is activated via PI3K in HGF-stimulated epithelial cells". Journal of Cell Science. 115 (Pt 20): 3947–56. doi:10.1242/jcs.00080. PMID 12244132.
  14. Bastea LI, Döppler H, Pearce SE, Durand N, Spratley SJ, Storz P (October 2013). "Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase 4". The Biochemical Journal. 455 (2): 251–60. doi:10.1042/BJ20130281. PMC 3880571. PMID 23841590.
  15. Spratley SJ, Bastea LI, Döppler H, Mizuno K, Storz P (September 2011). "Protein kinase D regulates cofilin activity through p21-activated kinase 4". The Journal of Biological Chemistry. 286 (39): 34254–61. doi:10.1074/jbc.M111.259424. PMC 3190831. PMID 21832093.
  16. Park MH, Lee HS, Lee CS, You ST, Kim DJ, Park BH, Kang MJ, Heo WD, Shin EY, Schwartz MA, Kim EG (May 2013). "p21-Activated kinase 4 promotes prostate cancer progression through CREB". Oncogene. 32 (19): 2475–82. doi:10.1038/onc.2012.255. PMID 22710715.
  17. Mak GW, Chan MM, Leong VY, Lee JM, Yau TO, Ng IO, Ching YP (April 2011). "Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis". Cancer Research. 71 (8): 2949–58. doi:10.1158/0008-5472.CAN-10-4046. PMID 21385901.
  18. Kim TW, Kang YK, Park ZY, Kim YH, Hong SW, Oh SJ, Sohn HA, Yang SJ, Jang YJ, Lee DC, Kim SY, Yoo HS, Kim E, Yeom YI, Park KC (March 2014). "SH3RF2 functions as an oncogene by mediating PAK4 protein stability". Carcinogenesis. 35 (3): 624–34. doi:10.1093/carcin/bgt338. PMID 24130170.
  19. 19.0 19.1 Ahmed T, Shea K, Masters JR, Jones GE, Wells CM (July 2008). "A PAK4-LIMK1 pathway drives prostate cancer cell migration downstream of HGF". Cellular Signalling. 20 (7): 1320–8. doi:10.1016/j.cellsig.2008.02.021. PMID 18424072.
  20. Li Z, Zhang H, Lundin L, Thullberg M, Liu Y, Wang Y, Claesson-Welsh L, Strömblad S (July 2010). "p21-activated kinase 4 phosphorylation of integrin beta5 Ser-759 and Ser-762 regulates cell migration". The Journal of Biological Chemistry. 285 (31): 23699–710. doi:10.1074/jbc.M110.123497. PMC 2911335. PMID 20507994.
  21. Wong LE, Reynolds AB, Dissanayaka NT, Minden A (August 2010). "p120-catenin is a binding partner and substrate for Group B Pak kinases". Journal of Cellular Biochemistry. 110 (5): 1244–54. doi:10.1002/jcb.22639. PMID 20564219.
  22. 22.0 22.1 22.2 Guo Q, Su N, Zhang J, Li X, Miao Z, Wang G, Cheng M, Xu H, Cao L, Li F (June 2014). "PAK4 kinase-mediated SCG10 phosphorylation involved in gastric cancer metastasis". Oncogene. 33 (25): 3277–87. doi:10.1038/onc.2013.296. PMID 23893240.
  23. Wells CM, Whale AD, Parsons M, Masters JR, Jones GE (May 2010). "PAK4: a pluripotent kinase that regulates prostate cancer cell adhesion". Journal of Cell Science. 123 (Pt 10): 1663–73. doi:10.1242/jcs.055707. PMC 2864712. PMID 20406887.
  24. 24.0 24.1 Wang C, Li Y, Zhang H, Liu F, Cheng Z, Wang D, Wang G, Xu H, Zhao Y, Cao L, Li F (June 2014). "Oncogenic PAK4 regulates Smad2/3 axis involving gastric tumorigenesis". Oncogene. 33 (26): 3473–84. doi:10.1038/onc.2013.300. PMID 23934187.
  25. Zhang HJ, Siu MK, Yeung MC, Jiang LL, Mak VC, Ngan HY, Wong OG, Zhang HQ, Cheung AN (May 2011). "Overexpressed PAK4 promotes proliferation, migration and invasion of choriocarcinoma". Carcinogenesis. 32 (5): 765–71. doi:10.1093/carcin/bgr033. PMID 21325635.
  26. Li Y, Wang D, Zhang H, Wang C, Dai W, Cheng Z, Wang G, Li F (October 2013). "P21-activated kinase 4 regulates the cyclin-dependent kinase inhibitor p57(kip2) in human breast cancer". Anatomical Record. 296 (10): 1561–7. doi:10.1002/ar.22754. PMID 23873832.
  27. Murray BW, Guo C, Piraino J, Westwick JK, Zhang C, Lamerdin J, Dagostino E, Knighton D, Loi CM, Zager M, Kraynov E, Popoff I, Christensen JG, Martinez R, Kephart SE, Marakovits J, Karlicek S, Bergqvist S, Smeal T (May 2010). "Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth". Proceedings of the National Academy of Sciences of the United States of America. 107 (20): 9446–51. doi:10.1073/pnas.0911863107. PMC 2889050. PMID 20439741.
  28. Zhang J, Wang J, Guo Q, Wang Y, Zhou Y, Peng H, Cheng M, Zhao D, Li F (April 2012). "LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells". Cancer Letters. 317 (1): 24–32. doi:10.1016/j.canlet.2011.11.007. PMID 22085492.
  29. Yeo D, Huynh N, Beutler JA, Christophi C, Shulkes A, Baldwin GS, Nikfarjam M, He H (May 2014). "Glaucarubinone and gemcitabine synergistically reduce pancreatic cancer growth via down-regulation of P21-activated kinases". Cancer Letters. 346 (2): 264–72. doi:10.1016/j.canlet.2014.01.001. PMID 24491405.
  30. Ryu BJ, Kim S, Min B, Kim KY, Lee JS, Park WJ, Lee H, Kim SH, Park S (July 2014). "Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor". Cancer Letters. 349 (1): 45–50. doi:10.1016/j.canlet.2014.03.024. PMID 24704155.
  31. Park JK, Kim S, Han YJ, Kim SH, Kang NS, Lee H, Park S (June 2016). "The discovery and the structural basis of an imidazo[4,5-b]pyridine-based p21-activated kinase 4 inhibitor". Bioorganic & Medicinal Chemistry Letters. 26 (11): 2580–3. doi:10.1016/j.bmcl.2016.04.037. PMID 27117431.
  32. Song S, Li X, Guo J, Hao C, Feng Y, Guo B, Liu T, Zhang Q, Zhang Z, Li R, Wang J, Lin B, Li F, Zhao D, Cheng M (March 2015). "Design, synthesis and biological evaluation of 1-phenanthryl-tetrahydroisoquinoline derivatives as novel p21-activated kinase 4 (PAK4) inhibitors". Organic & Biomolecular Chemistry. 13 (12): 3803–18. doi:10.1039/c5ob00037h. PMID 25705811.
  33. Guo B, Li X, Song S, Chen M, Cheng M, Zhao D, Li F (April 2016). "(-)-β-hydrastine suppresses the proliferation and invasion of human lung adenocarcinoma cells by inhibiting PAK4 kinase activity". Oncology Reports. 35 (4): 2246–56. doi:10.3892/or.2016.4594. PMID 26821251.
  34. Baskaran Y, Ang KC, Anekal PV, Chan WL, Grimes JM, Manser E, Robinson RC (November 2015). "An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1". Nature Communications. 6: 8681. doi:10.1038/ncomms9681. PMC 4674680. PMID 26607847.
  35. Zhang J, Zhang HY, Wang J, You LH, Zhou RZ, Zhao DM, Cheng MS, Li F (April 2016). "GL-1196 Suppresses the Proliferation and Invasion of Gastric Cancer Cells via Targeting PAK4 and Inhibiting PAK4-Mediated Signaling Pathways". International Journal of Molecular Sciences. 17 (4): 470. doi:10.3390/ijms17040470. PMC 4848926. PMID 27077843.
  36. Zhuang T, Zhu J, Li Z, Lorent J, Zhao C, Dahlman-Wright K, Strömblad S (December 2015). "p21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells". Oncotarget. 6 (41): 43853–68. doi:10.18632/oncotarget.6081. PMC 4791272. PMID 26554417.
  37. Wang Z, Zhang X, Yang Z, Du H, Wu Z, Gong J, Yan J, Zheng Q (October 2012). "MiR-145 regulates PAK4 via the MAPK pathway and exhibits an antitumor effect in human colon cells". Biochemical and Biophysical Research Communications. 427 (3): 444–9. doi:10.1016/j.bbrc.2012.06.123. PMID 22766504.
  38. Xue J, Chen LZ, Li ZZ, Hu YY, Yan SP, Liu LY (January 2015). "MicroRNA-433 inhibits cell proliferation in hepatocellular carcinoma by targeting p21 activated kinase (PAK4)". Molecular and Cellular Biochemistry. 399 (1–2): 77–86. doi:10.1007/s11010-014-2234-9. PMID 25410752.
  39. Luo P, Fei J, Zhou J, Zhang W (May 2015). "microRNA-126 suppresses PAK4 expression in ovarian cancer SKOV3 cells". Oncology Letters. 9 (5): 2225–2229. doi:10.3892/ol.2015.3012. PMC 4467333. PMID 26137045.
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  41. Qu J, Cammarano MS, Shi Q, Ha KC, de Lanerolle P, Minden A (May 2001). "Activated PAK4 regulates cell adhesion and anchorage-independent growth". Molecular and Cellular Biology. 21 (10): 3523–33. doi:10.1128/MCB.21.10.3523-3533.2001. PMC 100274. PMID 11313478.
  42. 42.0 42.1 Zhang H, Li Z, Viklund EK, Strömblad S (September 2002). "P21-activated kinase 4 interacts with integrin alpha v beta 5 and regulates alpha v beta 5-mediated cell migration". The Journal of Cell Biology. 158 (7): 1287–97. doi:10.1083/jcb.200207008. PMC 2173231. PMID 12356872.
  43. Gnesutta N, Qu J, Minden A (April 2001). "The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis". The Journal of Biological Chemistry. 276 (17): 14414–9. doi:10.1074/jbc.M011046200. PMID 11278822.
  44. Qu J, Li X, Novitch BG, Zheng Y, Kohn M, Xie JM, Kozinn S, Bronson R, Beg AA, Minden A (October 2003). "PAK4 kinase is essential for embryonic viability and for proper neuronal development". Molecular and Cellular Biology. 23 (20): 7122–33. doi:10.1128/mcb.23.20.7122-7133.2003. PMC 230313. PMID 14517283.
  45. Tyagi N, Marimuthu S, Bhardwaj A, Deshmukh SK, Srivastava SK, Singh AP, McClellan S, Carter JE, Singh S (January 2016). "p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling". Cancer Letters. 370 (2): 260–7. doi:10.1016/j.canlet.2015.10.028. PMC 4684758. PMID 26546043.
  46. Paliouras GN, Naujokas MA, Park M (June 2009). "Pak4, a novel Gab1 binding partner, modulates cell migration and invasion by the Met receptor". Molecular and Cellular Biology. 29 (11): 3018–32. doi:10.1128/MCB.01286-08. PMC 2682017. PMID 19289496.
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  49. Dan C, Kelly A, Bernard O, Minden A (August 2001). "Cytoskeletal changes regulated by the PAK4 serine/threonine kinase are mediated by LIM kinase 1 and cofilin". The Journal of Biological Chemistry. 276 (34): 32115–21. doi:10.1074/jbc.M100871200. PMID 11413130.

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