PAK5

Last updated

PAK5
Protein PAK7 PDB 2f57.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PAK5 , PAK7, p21 (RAC1) activated kinase 7, p21 (RAC1) activated kinase 5
External IDs OMIM: 608038; MGI: 1920334; HomoloGene: 22211; GeneCards: PAK5; OMA:PAK5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

57144

241656

Ensembl

ENSG00000101349

ENSMUSG00000039913

UniProt

Q9P286

Q8C015

RefSeq (mRNA)

NM_020341
NM_177990

NM_172858
NM_001360382
NM_001360384

RefSeq (protein)

NP_065074
NP_817127

NP_766446
NP_001347311
NP_001347313

Location (UCSC) Chr 20: 9.54 – 9.84 Mb Chr 2: 135.92 – 136.23 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Serine/threonine-protein kinase PAK 5 is an enzyme that in humans is encoded by the PAK5 gene. [5] [6] [7]

Contents

The PAK5 enzyme is one of three members of Group II PAK family of serine/threonine kinases, [8] [9] and evolutionary conserved across species. [10]

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. [8] [9] Selectivity of PAK5 signaling was recognized by its ability to stimulate the JNK kinase but not p38 or ERK kinases. [9]

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. [11]

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. [7]

Genetic deletion of PAK5 with or without PAK6 deletion in mice has been shown to be associated with a defective locomotion, memory, and learning. [12] [13] PAK5 is co-expressed with DISC1, a psychosis risk gene, and the pathway is likely to be involved in modulating synapse plasticity. [14] 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. [15] 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. [16]

Upstream regulators

PAK5 expression is positively regulated by Aurora-A and both PAK5 and Aurora-A are co-upregulated in esophageal squamous carcinoma. [17] The levels of PAK5 are regulated by miR-129 in hepatocacinoma cancer cells, [18] and by the binding of the long non-coding RNA Colorectal neoplasia differentially expressed (CRNDE) to miR-186 in glioma cells. [19]

Downstream targets

PAK5 phosphorylates Pacsin-1 and Synaptojanin-1 and regulates synaptic vesicle trafficking. [20] PAK5-mediated phosphorylation of GATA1 at S161 and S187 contributes to Epithelial-mesenchymal transition. [21] PAK5 phosphorylation of p120-catenin at S288 plays a role in cytoskeleton remodeling. [22] In addition to the cytoplasm, the PAK5 also localizes in mitochondria and phosphorylates BAD at S112. [23] PAK5 inhibits the MARK2/Par1 activity and modulates microtubules dynamics. [24]

Clinical significance

PAK5 levels are upregulated in osteosarcoma, [25] hepatocellular carcinomas, [26] gastric cancer, [27] glioma, [28] esophageal squamous cell cancer, [29] colon cancer, [30] ovarian cancer, [31] and breast cancer. [32] There are also examples of gain-of-function activating PAK5 mutations in non-small-cell lung cancer lung cancer. [33] PAK5 promotes the cell survival and sensitivity of cancer cells to chemotherapy. [17] [31] [34] [35]

Notes

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000101349 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000039913 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Dan C, Nath N, Liberto M, Minden A (January 2002). "PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells". Molecular and Cellular Biology. 22 (2): 567–77. doi:10.1128/MCB.22.2.567-577.2002. PMC   139731 . PMID   11756552.
  6. ↑ Nagase T, Ishikawa K, Kikuno R, Hirosawa M, Nomura N, Ohara O (October 1999). "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. doi: 10.1093/dnares/6.5.337 . PMID   10574462.
  7. 1 2 "Entrez Gene: PAK7 p21(CDKN1A)-activated kinase 7".
  8. 1 2 Dan C, Nath N, Liberto M, Minden A (January 2002). "PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells". Molecular and Cellular Biology. 22 (2): 567–77. doi:10.1128/mcb.22.2.567-577.2002. PMC   139731 . PMID   11756552.
  9. 1 2 3 Pandey A, Dan I, Kristiansen TZ, Watanabe NM, Voldby J, Kajikawa E, Khosravi-Far R, Blagoev B, Mann M (May 2002). "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. doi: 10.1038/sj.onc.1205478 . PMID   12032833.
  10. ↑ Kumar A, Molli PR, Pakala SB, Bui Nguyen TM, Rayala SK, Kumar R (July 2009). "PAK thread from amoeba to mammals". Journal of Cellular Biochemistry. 107 (4): 579–85. doi:10.1002/jcb.22159. PMC   2718766 . PMID   19350548.
  11. ↑ Kumar R, Li DQ (2016). PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Vol. 130. pp. 137–209. doi:10.1016/bs.acr.2016.01.002. ISBN   9780128047897. PMID   27037753.{{cite book}}: |journal= ignored (help)
  12. ↑ Furnari MA, Jobes ML, Nekrasova T, Minden A, Wagner GC (2013). "Functional deficits in PAK5, PAK6 and PAK5/PAK6 knockout mice". PLOS ONE. 8 (4): e61321. Bibcode:2013PLoSO...861321F. doi: 10.1371/journal.pone.0061321 . PMC   3620390 . PMID   23593460.
  13. ↑ Nekrasova T, Jobes ML, Ting JH, Wagner GC, Minden A (October 2008). "Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion". Developmental Biology. 322 (1): 95–108. doi: 10.1016/j.ydbio.2008.07.006 . PMID   18675265.
  14. ↑ Morris DW, Pearson RD, Cormican P, Kenny EM, O'Dushlaine CT, Perreault LP, et al. (June 2014). "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. doi:10.1093/hmg/ddu025. PMC   4030770 . PMID   24474471.
  15. ↑ Furnari MA, Jobes ML, Nekrasova T, Minden A, Wagner GC (April 2014). "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. doi:10.1179/1476830513Y.0000000072. PMC   4365912 . PMID   23710594.
  16. ↑ 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 (September 2014). "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. Bibcode:2014PNAS..11113924F. doi: 10.1073/pnas.1402665111 . PMC   4183326 . PMID   25201977.
  17. 1 2 He S, Feng M, Liu M, Yang S, Yan S, Zhang W, Wang Z, Hu C, Xu Q, Chen L, Zhu H, Xu N (1 December 2014). "P21-activated kinase 7 mediates cisplatin-resistance of esophageal squamous carcinoma cells with Aurora-A overexpression". PLOS ONE. 9 (12): e113989. Bibcode:2014PLoSO...9k3989H. doi: 10.1371/journal.pone.0113989 . PMC   4250179 . PMID   25436453.
  18. ↑ Zhai J, Qu S, Li X, Zhong J, Chen X, Qu Z, Wu D (August 2015). "miR-129 suppresses tumor cell growth and invasion by targeting PAK5 in hepatocellular carcinoma". Biochemical and Biophysical Research Communications. 464 (1): 161–7. doi:10.1016/j.bbrc.2015.06.108. PMID   26116538.
  19. ↑ Zheng J, Li XD, Wang P, Liu XB, Xue YX, Hu Y, Li Z, Li ZQ, Wang ZH, Liu YH (September 2015). "CRNDE affects the malignant biological characteristics of human glioma stem cells by negatively regulating miR-186". Oncotarget. 6 (28): 25339–55. doi:10.18632/oncotarget.4509. PMC   4694835 . PMID   26231038.
  20. ↑ Strochlic TI, Concilio S, Viaud J, Eberwine RA, Wong LE, Minden A, Turk BE, Plomann M, Peterson JR (March 2012). "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. Bibcode:2012PNAS..109.4116S. doi: 10.1073/pnas.1116560109 . PMC   3306725 . PMID   22371566.
  21. ↑ Li Y, Ke Q, Shao Y, Zhu G, Li Y, Geng N, Jin F, Li F (February 2015). "GATA1 induces epithelial-mesenchymal transition in breast cancer cells through PAK5 oncogenic signaling". Oncotarget. 6 (6): 4345–56. doi:10.18632/oncotarget.2999. PMC   4414194 . PMID   25726523.
  22. ↑ 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. S2CID   24567609.
  23. ↑ Cotteret S, Jaffer ZM, Beeser A, Chernoff J (August 2003). "p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD". Molecular and Cellular Biology. 23 (16): 5526–39. doi:10.1128/mcb.23.16.5526-5539.2003. PMC   166342 . PMID   12897128.
  24. ↑ Matenia D, Griesshaber B, Li XY, Thiessen A, Johne C, Jiao J, Mandelkow E, Mandelkow EM (September 2005). "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. doi:10.1091/mbc.E05-01-0081. PMC   1196348 . PMID   16014608.
  25. ↑ Han K, Zhou Y, Gan ZH, Qi WX, Zhang JJ, Fen T, Meng W, Jiang L, Shen Z, Min DL (December 2014). "p21-activated kinase 7 is an oncogene in human osteosarcoma". Cell Biology International. 38 (12): 1394–402. doi:10.1002/cbin.10351. PMC   4410679 . PMID   25052921.
  26. ↑ Fang ZP, Jiang BG, Gu XF, Zhao B, Ge RL, Zhang FB (January 2014). "P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma". Acta Pharmacologica Sinica. 35 (1): 82–8. doi:10.1038/aps.2013.31. PMC   4075737 . PMID   23685956.
  27. ↑ 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 (January 2013). "A role for p21-activated kinase 7 in the development of gastric cancer". The FEBS Journal. 280 (1): 46–55. doi: 10.1111/febs.12048 . PMID   23106939. S2CID   38130015.
  28. ↑ Gu X, Wang C, Wang X, Ma G, Li Y, Cui L, Chen Y, Zhao B, Li K (12 January 2015). "Efficient inhibition of human glioma development by RNA interference-mediated silencing of PAK5". International Journal of Biological Sciences. 11 (2): 230–7. doi:10.7150/ijbs.9193. PMC   4308408 . PMID   25632266.
  29. ↑ He S, Liu M, Zhang W, Xu N, Zhu H (2016). "Over expression of p21-activated kinase 7 associates with lymph node metastasis in esophageal squamous cell cancers". Cancer Biomarkers. 16 (2): 203–9. doi:10.3233/CBM-150557. PMID   26682509.
  30. ↑ Gong W, An Z, Wang Y, Pan X, Fang W, Jiang B, Zhang H (August 2009). "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. doi: 10.1002/ijc.24428 . PMID   19415746. S2CID   42711385.
  31. 1 2 Li D, Yao X, Zhang P (November 2013). "The overexpression of P21-activated kinase 5 (PAK5) promotes paclitaxel-chemoresistance of epithelial ovarian cancer". Molecular and Cellular Biochemistry. 383 (1–2): 191–9. doi:10.1007/s11010-013-1767-7. PMID   23877225. S2CID   5938617.
  32. ↑ Wang XX, Cheng Q, Zhang SN, Qian HY, Wu JX, Tian H, Pei DS, Zheng JN (October 2013). "PAK5-Egr1-MMP2 signaling controls the migration and invasion in breast cancer cell". Tumour Biology. 34 (5): 2721–9. doi:10.1007/s13277-013-0824-x. PMID   23696025. S2CID   15521185.
  33. ↑ Fawdar S, Trotter EW, Li Y, Stephenson NL, Hanke F, Marusiak AA, Edwards ZC, Ientile S, Waszkowycz B, Miller CJ, Brognard J (July 2013). "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. Bibcode:2013PNAS..11012426F. doi: 10.1073/pnas.1305207110 . PMC   3725071 . PMID   23836671.
  34. ↑ Wang X, Gong W, Qing H, Geng Y, Wang X, Zhang Y, Peng L, Zhang H, Jiang B (December 2010). "p21-activated kinase 5 inhibits camptothecin-induced apoptosis in colorectal carcinoma cells". Tumour Biology. 31 (6): 575–82. doi:10.1007/s13277-010-0071-3. PMID   20567954. S2CID   6344093.
  35. ↑ Zhang DG, Zhang J, Mao LL, Wu JX, Cao WJ, Zheng JN, Pei DS (May 2015). "p21-Activated kinase 5 affects cisplatin-induced apoptosis and proliferation in hepatocellular carcinoma cells". Tumour Biology. 36 (5): 3685–91. doi:10.1007/s13277-014-3007-5. PMID   25560489. S2CID   11752910.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.