PAK1

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PAK1
Protein PAK1 PDB 1e0a.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PAK1, PAKalpha, p21 (RAC1) activated kinase 1
External IDs MGI: 1339975 HomoloGene: 1936 GeneCards: 5058
RNA expression pattern
PBB GE PAK1 209615 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001128620
NM_002576

NM_011035

RefSeq (protein)

NP_001122092.1
NP_002567.3

n/a

Location (UCSC) Chr 11: 77.32 – 77.47 Mb Chr 7: 97.79 – 97.91 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.[1][2]

Function[edit]

PAK proteins are critical effectors that link the Rho_family_of_GTPases (Rho GTPases) to cytoskeleton reorganization and nuclear signaling. PAK proteins, a family of serine/threonine p21-activated kinases, include PAK1, PAK2, PAK3 and PAK4. These proteins serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK1 regulates cell motility and morphology. Alternative transcripts of this gene have been found, but their full-length natures have not been determined.[3]

Interactions[edit]

PAK1 has been shown to interact with:

Activation/inhibition[edit]

PAK1 contains an autoinhibitory domain that suppresses the catalytic activity of its kinase domain. PAK1 activators relieve this autoinhibition and initiate conformational rearrangements and autoPhosphorylation events leading to kinase activation.

IPA-3 inhibits PAK1. Preactivated PAK1 is resistant to IPA-3. Inhibition in live cells supports a critical role for PAK in PDGF-stimulated ERK activation.[18] Reversible covalent binding of IPA-3 to the PAK1 regulatory domain prevents GTPase docking and the subsequent switch to a catalytically active state.[19]

PAK1 knockdown in prostate cancer cells is associated with reduced motility, reduced MMP9 secretion and increased TGFβ expression, which in these cases, is growth inhibitory. However, IPA-3's pharmacokinetic properties as well as undesirable redox effects in cells, due to the continuous reduction of the sulfhydryl moiety, make it unsuitable for clinical development.[19]

References[edit]

  1. ^ Brown JL, Stowers L, Baer M, Trejo J, Coughlin S, Chant J (May 1996). "Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway". Current Biology 6 (5): 598–605. doi:10.1016/S0960-9822(02)00546-8. PMID 8805275. 
  2. ^ Bekri S, Adélaïde J, Merscher S, Grosgeorge J, Caroli-Bosc F, Perucca-Lostanlen D, Kelley PM, Pébusque MJ, Theillet C, Birnbaum D, Gaudray P (Apr 1998). "Detailed map of a region commonly amplified at 11q13-->q14 in human breast carcinoma". Cytogenetics and Cell Genetics 79 (1-2): 125–31. doi:10.1159/000134699. PMID 9533029. 
  3. ^ "Entrez Gene: PAK1 p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)". 
  4. ^ Zenke FT, Krendel M, DerMardirossian C, King CC, Bohl BP, Bokoch GM (April 2004). "p21-activated kinase 1 phosphorylates and regulates 14-3-3 binding to GEF-H1, a microtubule-localized Rho exchange factor". The Journal of Biological Chemistry 279 (18): 18392–400. doi:10.1074/jbc.M400084200. PMID 14970201. 
  5. ^ Vadlamudi RK, Li F, Barnes CJ, Bagheri-Yarmand R, Kumar R (February 2004). "p41-Arc subunit of human Arp2/3 complex is a p21-activated kinase-1-interacting substrate". EMBO Reports 5 (2): 154–60. doi:10.1038/sj.embor.7400079. PMC 1298990. PMID 14749719. 
  6. ^ Bagheri-Yarmand R, Mandal M, Taludker AH, Wang RA, Vadlamudi RK, Kung HJ, Kumar R (August 2001). "Etk/Bmx tyrosine kinase activates Pak1 and regulates tumorigenicity of breast cancer cells". The Journal of Biological Chemistry 276 (31): 29403–9. doi:10.1074/jbc.M103129200. PMID 11382770. 
  7. ^ Zang M, Hayne C, Luo Z (February 2002). "Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1". The Journal of Biological Chemistry 277 (6): 4395–405. doi:10.1074/jbc.M110000200. PMID 11733498. 
  8. ^ a b Seoh ML, Ng CH, Yong J, Lim L, Leung T (March 2003). "ArhGAP15, a novel human RacGAP protein with GTPase binding property". FEBS Letters 539 (1-3): 131–7. doi:10.1016/s0014-5793(03)00213-8. PMID 12650940. 
  9. ^ a b Zhang B, Chernoff J, Zheng Y (April 1998). "Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA". The Journal of Biological Chemistry 273 (15): 8776–82. doi:10.1074/jbc.273.15.8776. PMID 9535855. 
  10. ^ Rashid T, Banerjee M, Nikolic M (December 2001). "Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology". The Journal of Biological Chemistry 276 (52): 49043–52. doi:10.1074/jbc.M105599200. PMID 11604394. 
  11. ^ Vadlamudi RK, Bagheri-Yarmand R, Yang Z, Balasenthil S, Nguyen D, Sahin AA, den Hollander P, Kumar R (June 2004). "Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes cancerous phenotypes". Cancer Cell 5 (6): 575–85. doi:10.1016/j.ccr.2004.05.022. PMID 15193260. 
  12. ^ Edwards DC, Sanders LC, Bokoch GM, Gill GN (September 1999). "Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics". Nature Cell Biology 1 (5): 253–9. doi:10.1038/12963. PMID 10559936. 
  13. ^ Ku GM, Yablonski D, Manser E, Lim L, Weiss A (February 2001). "A PAK1-PIX-PKL complex is activated by the T-cell receptor independent of Nck, Slp-76 and LAT". The EMBO Journal 20 (3): 457–65. doi:10.1093/emboj/20.3.457. PMC 133476. PMID 11157752. 
  14. ^ Braverman LE, Quilliam LA (February 1999). "Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck". The Journal of Biological Chemistry 274 (9): 5542–9. doi:10.1074/jbc.274.9.5542. PMID 10026169. 
  15. ^ Bokoch GM, Wang Y, Bohl BP, Sells MA, Quilliam LA, Knaus UG (October 1996). "Interaction of the Nck adapter protein with p21-activated kinase (PAK1)". The Journal of Biological Chemistry 271 (42): 25746–9. doi:10.1074/jbc.271.42.25746. PMID 8824201. 
  16. ^ Xia C, Ma W, Stafford LJ, Marcus S, Xiong WC, Liu M (May 2001). "Regulation of the p21-activated kinase (PAK) by a human Gbeta -like WD-repeat protein, hPIP1". Proceedings of the National Academy of Sciences of the United States of America 98 (11): 6174–9. doi:10.1073/pnas.101137298. PMC 33441. PMID 11371639. 
  17. ^ Katoh H, Negishi M (July 2003). "RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo". Nature 424 (6947): 461–4. doi:10.1038/nature01817. PMID 12879077. 
  18. ^ Deacon SW, Beeser A, Fukui JA, Rennefahrt UE, Myers C, Chernoff J, Peterson JR (April 2008). "An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase". Chemistry & Biology 15 (4): 322–31. doi:10.1016/j.chembiol.2008.03.005. PMC 4353635. PMID 18420139. 
  19. ^ a b Goc, Anna; Al-Azayzih, Ahmad; Abdalla, Maha; Al-Husein, Belal; Kavuri, Sravankumar; Lee, Jeffrey; Moses, Kelvin; Somanath, Payaningal R. (2013-02-01). "P21 Activated Kinase-1 (Pak1) Promotes Prostate Tumor Growth and Microinvasion via Inhibition of Transforming Growth Factor β Expression and Enhanced Matrix Metalloproteinase 9 Secretion". Journal of Biological Chemistry 288 (5): 3025–3035. doi:10.1074/jbc.M112.424770. ISSN 0021-9258. PMC 3561527. PMID 23258534. 

Further reading[edit]

External links[edit]