PAK5 explained

Serine/threonine-protein kinase PAK 5 is an enzyme that in humans is encoded by the PAK5 gene.[1] [2] [3]

The PAK5 enzyme is one of three members of Group II PAK family of serine/threonine kinases,[4] [5] and evolutionary conserved across species.[6]

Discovery

The PAK5 was initially cloned as a brain-specific kinase with a predominant expression in brain with a suggested role in neurite growth in neuronal cells. Selectivity of PAK5 signaling was recognized by its ability to stimulate the JNK kinase but not p38 or ERK kinases.

Gene and spliced variants

The PAK5 gene, the longest among the PAK family, contains a total of 12 exons of which four exons are for 5’-UTR and remaining 8 exons for protein coding(Gene from review). Alternative exon splicing of the PAK5 gene generates three transcripts, and one of the transcript encodes a 719 amino acids long protein(Gene from review). The exon splicing of the murine PAK5 gene generates three transcripts, two of which code an identical 719 amino acids long polypeptide while the 2.0-kb transcript is a non-coding RNA with retained intron.

Protein domains

Similar to PAK4, PAK5 consists of a kinase, a CDC42/Rac1 interactive binding (CRIB) motif.[7]

Function

The protein encoded by this gene is a member of the PAK family of Ser/Thr protein kinases. PAK family members are known to be effectors of Rac/Cdc42 GTPases, which have been implicated in the regulation of cytoskeletal dynamics, proliferation, and cell survival signaling. This kinase contains a CDC42/Rac1 interactive binding (CRIB) motif, and has been shown to bind CDC42 in the presence of GTP.

This kinase is predominantly expressed in brain. It is capable of promoting neurite outgrowth, and thus may play a role in neurite development. This kinase is associated with microtubule networks and induces microtubule stabilization. The subcellular localization of this kinase is tightly regulated during cell cycle progression. Alternatively spliced transcript variants encoding the same protein have been described.

Genetic deletion of PAK5 with or without PAK6 deletion in mice has been shown to be associated with a defective locomotion, memory, and learning.[8] [9] PAK5 is co-expressed with DISC1, a psychosis risk gene, and the pathway is likely to be involved in modulating synapse plasticity.[10] Physiological level of PAK5 is linked with an overall physical activity in mice as PAK5 deletion in mice has been shown to be associated with an increased activity upon amphetamine stimulation.[11] PAK5 has been also thought to be one of genetic variants regulating gene expression (eQTL) and its expression associates with an inhibited glucose-regulated secretion of insulin in INS1 cells.[12]

Upstream regulators

PAK5 expression is positively regulated by Aurora-A and both PAK5 and Aurora-A are co-upregulated in esophageal squamous carcinoma.[13] The levels of PAK5 are regulated by miR-129 in hepatocacinoma cancer cells,[14] and by the binding of the long non-coding RNA Colorectal neoplasia differentially expressed (CRNDE) to miR-186 in glioma cells.[15]

Downstream targets

PAK5 phosphorylates Pacsin-1 and Synaptojanin-1 and regulates synaptic vesicle trafficking.[16] PAK5-mediated phosphorylation of GATA1 at S161 and S187 contributes to Epithelial-mesenchymal transition.[17] PAK5 phosphorylation of p120-catenin at S288 plays a role in cytoskeleton remodeling.[18] In addition to the cytoplasm, the PAK5 also localizes in mitochondria and phosphorylates BAD at S112.[19] PAK5 inhibits the MARK2/Par1 activity and modulates microtubules dynamics.[20]

Clinical significance

PAK5 levels are upregulated in osteosarcoma,[21] hepatocellular carcinomas,[22] gastric cancer,[23] glioma,[24] esophageal squamous cell cancer,[25] colon cancer,[26] ovarian cancer,[27] and breast cancer.[28] There are also examples of gain-of-function activating PAK5 mutations in non-small-cell lung cancer lung cancer.[29] PAK5 promotes the cell survival and sensitivity of cancer cells to chemotherapy.[30] [31]

Notes and References

  1. Dan C, Nath N, Liberto M, Minden A . PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells . Molecular and Cellular Biology . 22 . 2 . 567–77 . January 2002 . 11756552 . 139731 . 10.1128/MCB.22.2.567-577.2002 .
  2. Nagase T, Ishikawa K, Kikuno R, Hirosawa M, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 6 . 5 . 337–45 . October 1999 . 10574462 . 10.1093/dnares/6.5.337 . free .
  3. Web site: Entrez Gene: PAK7 p21(CDKN1A)-activated kinase 7.
  4. Dan C, Nath N, Liberto M, Minden A . PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells . Molecular and Cellular Biology . 22 . 2 . 567–77 . January 2002 . 11756552 . 10.1128/mcb.22.2.567-577.2002 . 139731.
  5. Pandey A, Dan I, Kristiansen TZ, Watanabe NM, Voldby J, Kajikawa E, Khosravi-Far R, Blagoev B, Mann M . Cloning and characterization of PAK5, a novel member of mammalian p21-activated kinase-II subfamily that is predominantly expressed in brain . Oncogene . 21 . 24 . 3939–48 . May 2002 . 12032833 . 10.1038/sj.onc.1205478 . free .
  6. Kumar A, Molli PR, Pakala SB, Bui Nguyen TM, Rayala SK, Kumar R . PAK thread from amoeba to mammals . Journal of Cellular Biochemistry . 107 . 4 . 579–85 . July 2009 . 19350548 . 10.1002/jcb.22159 . 2718766.
  7. Book: Kumar R, Li DQ . PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology . Advances in Cancer Research . 130 . 137–209 . 2016 . 27037753 . 10.1016/bs.acr.2016.01.002 . 9780128047897 .
  8. Furnari MA, Jobes ML, Nekrasova T, Minden A, Wagner GC . Functional deficits in PAK5, PAK6 and PAK5/PAK6 knockout mice . PLOS ONE . 8 . 4 . e61321 . 2013 . 23593460 . 10.1371/journal.pone.0061321 . 3620390. free . 2013PLoSO...861321F .
  9. Nekrasova T, Jobes ML, Ting JH, Wagner GC, Minden A . Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion . Developmental Biology . 322 . 1 . 95–108 . October 2008 . 18675265 . 10.1016/j.ydbio.2008.07.006 . free .
  10. Morris DW, Pearson RD, Cormican P, Kenny EM, O'Dushlaine CT, Perreault LP, Giannoulatou E, Tropea D, Maher BS, Wormley B, Kelleher E, Fahey C, Molinos I, Bellini S, Pirinen M, Strange A, Freeman C, Thiselton DL, Elves RL, Regan R, Ennis S, Dinan TG, McDonald C, Murphy KC, O'Callaghan E, Waddington JL, Walsh D, O'Donovan M, Grozeva D, Craddock N, Stone J, Scolnick E, Purcell S, Sklar P, Coe B, Eichler EE, Ophoff R, Buizer J, Szatkiewicz J, Hultman C, Sullivan P, Gurling H, Mcquillin A, St Clair D, Rees E, Kirov G, Walters J, Blackwood D, Johnstone M, Donohoe G, O'Neill FA, Kendler KS, Gill M, Riley BP, Spencer CC, Corvin A . 6 . An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis . Human Molecular Genetics . 23 . 12 . 3316–26 . June 2014 . 24474471 . 10.1093/hmg/ddu025 . 4030770.
  11. Furnari MA, Jobes ML, Nekrasova T, Minden A, Wagner GC . Differential sensitivity of Pak5, Pak6, and Pak5/Pak6 double-knockout mice to the stimulant effects of amphetamine and exercise-induced alterations in body weight . Nutritional Neuroscience . 17 . 3 . 109–15 . April 2014 . 23710594 . 10.1179/1476830513Y.0000000072 . 4365912.
  12. Fadista J, Vikman P, Laakso EO, Mollet IG, Esguerra JL, Taneera J, Storm P, Osmark P, Ladenvall C, Prasad RB, Hansson KB, Finotello F, Uvebrant K, Ofori JK, Di Camillo B, Krus U, Cilio CM, Hansson O, Eliasson L, Rosengren AH, Renström E, Wollheim CB, Groop L . Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism . Proceedings of the National Academy of Sciences of the United States of America . 111 . 38 . 13924–9 . September 2014 . 25201977 . 10.1073/pnas.1402665111 . 4183326. free . 2014PNAS..11113924F .
  13. He S, Feng M, Liu M, Yang S, Yan S, Zhang W, Wang Z, Hu C, Xu Q, Chen L, Zhu H, Xu N . P21-activated kinase 7 mediates cisplatin-resistance of esophageal squamous carcinoma cells with Aurora-A overexpression . PLOS ONE . 9 . 12 . e113989 . 1 December 2014 . 25436453 . 10.1371/journal.pone.0113989 . 4250179. free . 2014PLoSO...9k3989H .
  14. Zhai J, Qu S, Li X, Zhong J, Chen X, Qu Z, Wu D . miR-129 suppresses tumor cell growth and invasion by targeting PAK5 in hepatocellular carcinoma . Biochemical and Biophysical Research Communications . 464 . 1 . 161–7 . August 2015 . 26116538 . 10.1016/j.bbrc.2015.06.108 .
  15. Zheng J, Li XD, Wang P, Liu XB, Xue YX, Hu Y, Li Z, Li ZQ, Wang ZH, Liu YH . CRNDE affects the malignant biological characteristics of human glioma stem cells by negatively regulating miR-186 . Oncotarget . 6 . 28 . 25339–55 . September 2015 . 26231038 . 10.18632/oncotarget.4509 . 4694835.
  16. Strochlic TI, Concilio S, Viaud J, Eberwine RA, Wong LE, Minden A, Turk BE, Plomann M, Peterson JR . Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking . Proceedings of the National Academy of Sciences of the United States of America . 109 . 11 . 4116–21 . March 2012 . 22371566 . 10.1073/pnas.1116560109 . 3306725. free . 2012PNAS..109.4116S .
  17. Li Y, Ke Q, Shao Y, Zhu G, Li Y, Geng N, Jin F, Li F . GATA1 induces epithelial-mesenchymal transition in breast cancer cells through PAK5 oncogenic signaling . Oncotarget . 6 . 6 . 4345–56 . February 2015 . 25726523 . 10.18632/oncotarget.2999 . 4414194.
  18. Wong LE, Reynolds AB, Dissanayaka NT, Minden A . p120-catenin is a binding partner and substrate for Group B Pak kinases . Journal of Cellular Biochemistry . 110 . 5 . 1244–54 . August 2010 . 20564219 . 10.1002/jcb.22639 . 24567609 .
  19. Cotteret S, Jaffer ZM, Beeser A, Chernoff J . p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD . Molecular and Cellular Biology . 23 . 16 . 5526–39 . August 2003 . 12897128 . 10.1128/mcb.23.16.5526-5539.2003 . 166342.
  20. Matenia D, Griesshaber B, Li XY, Thiessen A, Johne C, Jiao J, Mandelkow E, Mandelkow EM . PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin . Molecular Biology of the Cell . 16 . 9 . 4410–22 . September 2005 . 16014608 . 10.1091/mbc.E05-01-0081 . 1196348.
  21. Han K, Zhou Y, Gan ZH, Qi WX, Zhang JJ, Fen T, Meng W, Jiang L, Shen Z, Min DL . p21-activated kinase 7 is an oncogene in human osteosarcoma . Cell Biology International . 38 . 12 . 1394–402 . December 2014 . 25052921 . 10.1002/cbin.10351 . 4410679.
  22. Fang ZP, Jiang BG, Gu XF, Zhao B, Ge RL, Zhang FB . P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma . Acta Pharmacologica Sinica . 35 . 1 . 82–8 . January 2014 . 23685956 . 10.1038/aps.2013.31 . 4075737.
  23. Gu J, Li K, Li M, Wu X, Zhang L, Ding Q, Wu W, Yang J, Mu J, Wen H, Ding Q, Lu J, Hao Y, Chen L, Zhang W, Li S, Liu Y . A role for p21-activated kinase 7 in the development of gastric cancer . The FEBS Journal . 280 . 1 . 46–55 . January 2013 . 23106939 . 10.1111/febs.12048 . 38130015 . free .
  24. Gu X, Wang C, Wang X, Ma G, Li Y, Cui L, Chen Y, Zhao B, Li K . Efficient inhibition of human glioma development by RNA interference-mediated silencing of PAK5 . International Journal of Biological Sciences . 11 . 2 . 230–7 . 12 January 2015 . 25632266 . 10.7150/ijbs.9193 . 4308408.
  25. He S, Liu M, Zhang W, Xu N, Zhu H . Over expression of p21-activated kinase 7 associates with lymph node metastasis in esophageal squamous cell cancers . Cancer Biomarkers . 16 . 2 . 203–9 . 2016 . 26682509 . 10.3233/CBM-150557 .
  26. Gong W, An Z, Wang Y, Pan X, Fang W, Jiang B, Zhang H . P21-activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration . International Journal of Cancer . 125 . 3 . 548–55 . August 2009 . 19415746 . 10.1002/ijc.24428 . 42711385 . free .
  27. Li D, Yao X, Zhang P . The overexpression of P21-activated kinase 5 (PAK5) promotes paclitaxel-chemoresistance of epithelial ovarian cancer . Molecular and Cellular Biochemistry . 383 . 1–2 . 191–9 . November 2013 . 23877225 . 10.1007/s11010-013-1767-7 . 5938617 .
  28. Wang XX, Cheng Q, Zhang SN, Qian HY, Wu JX, Tian H, Pei DS, Zheng JN . PAK5-Egr1-MMP2 signaling controls the migration and invasion in breast cancer cell . Tumour Biology . 34 . 5 . 2721–9 . October 2013 . 23696025 . 10.1007/s13277-013-0824-x . 15521185 .
  29. Fawdar S, Trotter EW, Li Y, Stephenson NL, Hanke F, Marusiak AA, Edwards ZC, Ientile S, Waszkowycz B, Miller CJ, Brognard J . Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer . Proceedings of the National Academy of Sciences of the United States of America . 110 . 30 . 12426–31 . July 2013 . 23836671 . 10.1073/pnas.1305207110 . 3725071. free . 2013PNAS..11012426F .
  30. Wang X, Gong W, Qing H, Geng Y, Wang X, Zhang Y, Peng L, Zhang H, Jiang B . p21-activated kinase 5 inhibits camptothecin-induced apoptosis in colorectal carcinoma cells . Tumour Biology . 31 . 6 . 575–82 . December 2010 . 20567954 . 10.1007/s13277-010-0071-3 . 6344093 .
  31. Zhang DG, Zhang J, Mao LL, Wu JX, Cao WJ, Zheng JN, Pei DS . p21-Activated kinase 5 affects cisplatin-induced apoptosis and proliferation in hepatocellular carcinoma cells . Tumour Biology . 36 . 5 . 3685–91 . May 2015 . 25560489 . 10.1007/s13277-014-3007-5 . 11752910 .

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