PAK1

P21 protein (Cdc42/Rac)-activated kinase 1
PDB rendering based on 1e0a.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1F3M​, 1YHV​, 1YHW​, 1ZSG​, 2HY8​, 2QME​, 3DVP​, 3FXZ​, 3FY0​, 3Q4Z​, 3Q52​, 3Q53​, 4DAW​, 4EQC​, 4O0R​, 4O0T​, 4P90​
Identifiers
Symbols	PAK1 ; PAKalpha
External IDs	OMIM: 602590 MGI: 1339975 HomoloGene: 1936 ChEMBL: 4600 GeneCards: PAK1 Gene
EC number	2.7.11.1
Gene ontology Molecular function • protein kinase activity • protein serine/threonine kinase activity • protein binding • collagen binding • ATP binding • Rac GTPase binding Cellular component • ruffle • cytoplasm • Golgi apparatus • cytosol • plasma membrane • cell-cell junction • focal adhesion • intercalated disc • Z disc • axon • dendrite • growth cone • filamentous actin • nuclear membrane • ruffle membrane • protein complex • invadopodium • neuronal postsynaptic density Biological process • MAPK cascade • positive regulation of protein phosphorylation • stimulatory C-type lectin receptor signaling pathway • protein phosphorylation • exocytosis • apoptotic process • small GTPase mediated signal transduction • Rho protein signal transduction • regulation of mitotic cell cycle • axon guidance • neuromuscular junction development • dendrite development • cell migration • positive regulation of cell migration • stress-activated protein kinase signaling cascade • T cell costimulation • actin cytoskeleton reorganization • activation of protein kinase activity • positive regulation of peptidyl-serine phosphorylation • positive regulation of intracellular estrogen receptor signaling pathway • Fc-epsilon receptor signaling pathway • Fc-gamma receptor signaling pathway involved in phagocytosis • wound healing • regulation of apoptotic process • receptor clustering • positive regulation of JUN kinase activity • innate immune response • protein autophosphorylation • vascular endothelial growth factor receptor signaling pathway • ephrin receptor signaling pathway • branching morphogenesis of an epithelial tube • neuron projection morphogenesis • T cell receptor signaling pathway • positive regulation of stress fiber assembly • negative regulation of cell proliferation involved in contact inhibition Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5058	18479
Ensembl	ENSG00000149269	ENSMUSG00000030774
UniProt	Q13153	Q9R2B2
RefSeq (mRNA)	NM_001128620	NM_011035
RefSeq (protein)	NP_001122092	NP_035165
Location (UCSC)	Chr 11: 77.32 – 77.47 Mb	Chr 7: 97.84 – 97.91 Mb
PubMed search

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

Function

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

PAK1 has been shown to interact with:

• ARHGEF2,^[4]
• ARPC1B,^[5]
• BMX,^[6]
• C-Raf,^[7]
• CDC42,^[8][9]
• Cyclin-dependent kinase 5,^[10]
• DYNLL1,^[11]
• LIMK1,^[12]
• NCK1,^[13][14][15]
• PAK1IP1^[16] and
• RAC1.^[17][8][9]

Activation/inhibition

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

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. 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. 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. 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

• Trono D, Wang JK (January 1997). "Nef and PAK: virulence factor and cellular accomplice". Chemistry & Biology 4 (1): 13–5. doi:10.1016/S1074-5521(97)90232-5. PMID 9070423.
• 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.
• Geyer M, Fackler OT, Peterlin BM (July 2001). "Structure--function relationships in HIV-1 Nef". EMBO Reports 2 (7): 580–5. doi:10.1093/embo-reports/kve141. PMC 1083955. PMID 11463741.
• Jaffer ZM, Chernoff J (July 2002). "p21-activated kinases: three more join the Pak". The International Journal of Biochemistry & Cell Biology 34 (7): 713–7. doi:10.1016/S1357-2725(01)00158-3. PMID 11950587.
• Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M (April 2003). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". Journal of Biosciences 28 (3): 323–35. doi:10.1007/BF02970151. PMID 12734410.
• Joseph AM, Kumar M, Mitra D (January 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
• Anderson JL, Hope TJ (April 2004). "HIV accessory proteins and surviving the host cell". Current HIV/AIDS Reports 1 (1): 47–53. doi:10.1007/s11904-004-0007-x. PMID 16091223.
• Sheehan KA, Ke Y, Solaro RJ (September 2007). "p21-Activated kinase-1 and its role in integrated regulation of cardiac contractility". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 293 (3): R963–73. doi:10.1152/ajpregu.00253.2007. PMID 17609315.
• Martin GA, Bollag G, McCormick F, Abo A (May 1995). "A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20". The EMBO Journal 14 (9): 1970–8. PMC 398296. PMID 7744004.
• Sawai ET, Baur AS, Peterlin BM, Levy JA, Cheng-Mayer C (June 1995). "A conserved domain and membrane targeting of Nef from HIV and SIV are required for association with a cellular serine kinase activity". The Journal of Biological Chemistry 270 (25): 15307–14. doi:10.1074/jbc.270.25.15307. PMID 7797518.
• Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L (January 1994). "A brain serine/threonine protein kinase activated by Cdc42 and Rac1". Nature 367 (6458): 40–6. doi:10.1038/367040a0. PMID 8107774.
• Sawai ET, Baur A, Struble H, Peterlin BM, Levy JA, Cheng-Mayer C (February 1994). "Human immunodeficiency virus type 1 Nef associates with a cellular serine kinase in T lymphocytes". Proceedings of the National Academy of Sciences of the United States of America 91 (4): 1539–43. doi:10.1073/pnas.91.4.1539. PMC 43195. PMID 8108442.
• Nunn MF, Marsh JW (September 1996). "Human immunodeficiency virus type 1 Nef associates with a member of the p21-activated kinase family". Journal of Virology 70 (9): 6157–61. PMC 190639. PMID 8709241.
• Luo T, Garcia JV (September 1996). "The association of Nef with a cellular serine/threonine kinase and its enhancement of infectivity are viral isolate dependent". Journal of Virology 70 (9): 6493–6. PMC 190686. PMID 8709288.
• 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.
• Wiskerchen M, Cheng-Mayer C (October 1996). "HIV-1 Nef association with cellular serine kinase correlates with enhanced virion infectivity and efficient proviral DNA synthesis". Virology 224 (1): 292–301. doi:10.1006/viro.1996.0531. PMID 8862424.
• Sawai ET, Khan IH, Montbriand PM, Peterlin BM, Cheng-Mayer C, Luciw PA (November 1996). "Activation of PAK by HIV and SIV Nef: importance for AIDS in rhesus macaques". Current Biology 6 (11): 1519–27. doi:10.1016/S0960-9822(96)00757-9. PMID 8939608.
• Manser E, Huang HY, Loo TH, Chen XQ, Dong JM, Leung T, Lim L (March 1997). "Expression of constitutively active alpha-PAK reveals effects of the kinase on actin and focal complexes". Molecular and Cellular Biology 17 (3): 1129–43. PMC 231838. PMID 9032240.

External links

• PAK1 Info with links in the Cell Migration Gateway
• Andrei, Mihai (March 23, 2016). "Researchers zoom in on potential treatment for prostate cancer". ZME Science. Retrieved 2016-04-23.