PAK2 explained

Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.[1] [2]

PAK2 is one of three members of Group I PAK family of serine/threonine kinases.[3] [4] The PAKs are evolutionary conserved.[5] PAK2 and its cleaved fragment localize in both the cytoplasmic or nuclear compartments. PAK2 signaling modulates apoptosis,[6] endothelial lumen formation,[7] viral pathogenesis,[8] and cancer including, breast,[9] hepatocarcinoma,[10] gastric [11] and cancer, at-large,[12] and, based on its kinase activity alone, peripheral nerve myelination during embryonic development. [13]

Discovery

The human PAK2 was identified as a downstream effector of Rac or Cdc42.

Gene and spliced variants

The PAK2 gene is about 92.7-kb long. The gene contains 15 exons and generates three alternatively spliced transcripts - two of which code proteins of 524 amino acids and 221 amino acids, while the third one is a 371-bp non-coding RNA transcript(Gene from review) There are two transcripts generated from the murine PAK2 gene, a 5.7-kb transcript coding a 524 amino acids long polypeptide and a 1.2-kb long non-coding RNA transcript.

Protein domains

Similar to PAK1, PAK2 contains a p21-binding domain (PBD) and an auto-inhibitory domain (AID) and exists in an inactive conformation.

The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell.[14]

Function

The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell.[15] Finally, while both PAK 1 and PAK 2 proteins have been shown to be elevated during the embryonic phase, PAK 2 kinase activity specifically has been demonstrated to be a requirement during the myelenation of developing nerves.

Upstream activators

PAK2 kinase activity is stimulated by transforming growth factor β in fibroblasts,[16] by proteinase inhibitor alpha2-macroglobulin binding to GRP78 in prostate cancer cells,[17] by its phosphorylation by AMP-activated protein kinase in stem and cancer cells [18] and eryptosis.[19] PAK2 is cleaved through activated caspase-3 in fibroblast and cancer cells exposed to ultraviolet,[20] hyperosmotic shock,[21] and ionizing radiation.[22]

Inhibitors

The levels of PAK2 activation in experimental systems are inhibited by synthetic PAK-inhibitors and miRs. For example, FRAX1036 differentially inhibits PAK2 and PAK1 activities;[23] FRAX597 suppresses PAK2 activity in neurofibromatosis type 2 (NF2)-associated tumorigenesis;[24] and miR-23b and miR-137 inhibits PAK2 expression in tumor cells.[25] [26] Insulin stimulation of neuronal cells also antagonizes PAK2 kinase activity, leading to an increased glucose uptake.[27]

Downstream targets

PAK2-mediated phosphorylation of merlin at S518 modulates its tumor suppressor activity,[28] c-Jun phosphorylation at T2, T8, T89, T93 and T286 contributes to the growth of growth factor-stimulated melanoma cells,[29] Caspase-7 phosphorylation at S30, T173 and S239 inhibits apoptotic activity in breast cancer cells, Paxillin phosphorylation at S272 and S274 activates ADAM10 protease,[30] and STAT5 phosphorylation at S779 modulates BCL-ABL-mediated leukemogenesis.[31] PAK2 activity negatively regulates the function and expression of c-Myc: PAK2 phosphorylation of c-Myc at T358-S373-T400 inhibits its transactivation function [32] and PAK2 depletion stimulates c-Myc expression during granulocyte-monocyte lineage.[33]

External links

Notes and References

  1. Martin GA, Bollag G, McCormick F, Abo A . A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20 . The EMBO Journal . 14 . 9 . 1970–8 . May 1995 . 7744004 . 398296 . 10.1002/j.1460-2075.1995.tb07189.x.
  2. Knaus UG, Morris S, Dong HJ, Chernoff J, Bokoch GM . Regulation of human leukocyte p21-activated kinases through G protein--coupled receptors . Science . 269 . 5221 . 221–3 . July 1995 . 7618083 . 10.1126/science.7618083 . 1995Sci...269..221K .
  3. Knaus UG, Morris S, Dong HJ, Chernoff J, Bokoch GM . Regulation of human leukocyte p21-activated kinases through G protein--coupled receptors . Science . 269 . 5221 . 221–3 . July 1995 . 7618083 . 10.1126/science.7618083. 1995Sci...269..221K .
  4. Manser E, Chong C, Zhao ZS, Leung T, Michael G, Hall C, Lim L . Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family . The Journal of Biological Chemistry . 270 . 42 . 25070–8 . October 1995 . 7559638 . 10.1074/jbc.270.42.25070. free .
  5. 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.
  6. Bokoch GM . Caspase-mediated activation of PAK2 during apoptosis: proteolytic kinase activation as a general mechanism of apoptotic signal transduction? . Cell Death and Differentiation . 5 . 8 . 637–45 . August 1998 . 10200518 . 10.1038/sj.cdd.4400405 . free .
  7. Davis GE, Koh W, Stratman AN . Mechanisms controlling human endothelial lumen formation and tube assembly in three-dimensional extracellular matrices . Birth Defects Research. Part C, Embryo Today . 81 . 4 . 270–85 . December 2007 . 18228260 . 10.1002/bdrc.20107 .
  8. Van den Broeke C, Radu M, Chernoff J, Favoreel HW . An emerging role for p21-activated kinases (Paks) in viral infections . Trends in Cell Biology . 20 . 3 . 160–9 . March 2010 . 20071173 . 10.1016/j.tcb.2009.12.005 . 6489496 .
  9. Li X, Wen W, Liu K, Zhu F, Malakhova M, Peng C, Li T, Kim HG, Ma W, Cho YY, Bode AM, Dong Z, Dong Z . Phosphorylation of caspase-7 by p21-activated protein kinase (PAK) 2 inhibits chemotherapeutic drug-induced apoptosis of breast cancer cell lines . The Journal of Biological Chemistry . 286 . 25 . 22291–9 . June 2011 . 21555521 . 10.1074/jbc.M111.236596 . 3121375. free .
  10. Sato M, Matsuda Y, Wakai T, Kubota M, Osawa M, Fujimaki S, Sanpei A, Takamura M, Yamagiwa S, Aoyagi Y . P21-activated kinase-2 is a critical mediator of transforming growth factor-β-induced hepatoma cell migration . Journal of Gastroenterology and Hepatology . 28 . 6 . 1047–55 . June 2013 . 23425030 . 10.1111/jgh.12150 . 23620441 .
  11. Gao C, Ma T, Pang L, Xie R . Activation of P21-activated protein kinase 2 is an independent prognostic predictor for patients with gastric cancer . Diagnostic Pathology . 9 . 55 . March 2014 . 24621074 . 10.1186/1746-1596-9-55 . 3975179 . free .
  12. 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 . 978-0-12-804789-7 .
  13. PAK2 is necessary for myelination in the peripheral nervous system . 2024-08-07 . Brain . 2024 . 10.1093/brain/awad413 . 11068108 . 38079473 . 147 . 5 . 1809–1821 . Hu B, Moiseev D, Schena I, Faezov B, Dunbrack R, Chernoff J, Li J .
  14. Web site: Entrez Gene: PAK2 p21 (CDKN1A)-activated kinase 2.
  15. Web site: Entrez Gene: PAK2 p21 (CDKN1A)-activated kinase 2.
  16. Wilkes MC, Murphy SJ, Garamszegi N, Leof EB . Cell-type-specific activation of PAK2 by transforming growth factor beta independent of Smad2 and Smad3 . Molecular and Cellular Biology . 23 . 23 . 8878–89 . December 2003 . 14612425 . 10.1128/mcb.23.23.8878-8889.2003 . 262664.
  17. Misra UK, Deedwania R, Pizzo SV . Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK . The Journal of Biological Chemistry . 280 . 28 . 26278–86 . July 2005 . 15908432 . 10.1074/jbc.M414467200 . 1201553. free .
  18. Banko MR, Allen JJ, Schaffer BE, Wilker EW, Tsou P, White JL, Villén J, Wang B, Kim SR, Sakamoto K, Gygi SP, Cantley LC, Yaffe MB, Shokat KM, Brunet A . Chemical genetic screen for AMPKα2 substrates uncovers a network of proteins involved in mitosis . Molecular Cell . 44 . 6 . 878–92 . December 2011 . 22137581 . 10.1016/j.molcel.2011.11.005 . 3246132.
  19. Zelenak C, Föller M, Velic A, Krug K, Qadri SM, Viollet B, Lang F, Macek B . Proteome analysis of erythrocytes lacking AMP-activated protein kinase reveals a role of PAK2 kinase in eryptosis . Journal of Proteome Research . 10 . 4 . 1690–7 . April 2011 . 21214270 . 10.1021/pr101004j .
  20. Tang TK, Chang WC, Chan WH, Yang SD, Ni MH, Yu JS . Proteolytic cleavage and activation of PAK2 during UV irradiation-induced apoptosis in A431 cells . Journal of Cellular Biochemistry . 70 . 4 . 442–54 . September 1998 . 9712143 . 10.1002/(sici)1097-4644(19980915)70:4<442::aid-jcb2>3.3.co;2-n.
  21. Chan WH, Yu JS, Yang SD . PAK2 is cleaved and activated during hyperosmotic shock-induced apoptosis via a caspase-dependent mechanism: evidence for the involvement of oxidative stress . Journal of Cellular Physiology . 178 . 3 . 397–408 . March 1999 . 9989786 . 10.1002/(SICI)1097-4652(199903)178:3<397::AID-JCP14>3.0.CO;2-2 . 35684065 .
  22. Roig J, Traugh JA . p21-activated protein kinase gamma-PAK is activated by ionizing radiation and other DNA-damaging agents. Similarities and differences to alpha-PAK . The Journal of Biological Chemistry . 274 . 44 . 31119–22 . October 1999 . 10531298 . 10.1074/jbc.274.44.31119. free .
  23. Ong CC, Gierke S, Pitt C, Sagolla M, Cheng CK, Zhou W, Jubb AM, Strickland L, Schmidt M, Duron SG, Campbell DA, Zheng W, Dehdashti S, Shen M, Yang N, Behnke ML, Huang W, McKew JC, Chernoff J, Forrest WF, Haverty PM, Chin SF, Rakha EA, Green AR, Ellis IO, Caldas C, O'Brien T, Friedman LS, Koeppen H, Rudolph J, Hoeflich KP . 6 . Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents . Breast Cancer Research . 17 . 59 . April 2015 . 1 . 25902869 . 10.1186/s13058-015-0564-5 . 4445529 . free .
  24. Licciulli S, Maksimoska J, Zhou C, Troutman S, Kota S, Liu Q, Duron S, Campbell D, Chernoff J, Field J, Marmorstein R, Kissil JL . FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas . The Journal of Biological Chemistry . 288 . 40 . 29105–14 . October 2013 . 23960073 . 10.1074/jbc.M113.510933 . 3790009. free .
  25. Pellegrino L, Krell J, Roca-Alonso L, Stebbing J, Castellano L . MicroRNA-23b regulates cellular architecture and impairs motogenic and invasive phenotypes during cancer progression . Bioarchitecture . 3 . 4 . 119–24 . 2012 . 24002530 . 10.4161/bioa.26134 . 4201606.
  26. Hao S, Luo C, Abukiwan A, Wang G, He J, Huang L, Weber CE, Lv N, Xiao X, Eichmüller SB, He D . miR-137 inhibits proliferation of melanoma cells by targeting PAK2 . Experimental Dermatology . 24 . 12 . 947–52 . December 2015 . 26186482 . 10.1111/exd.12812 . 29618231 .
  27. Varshney P, Dey CS . P21-activated kinase 2 (PAK2) regulates glucose uptake and insulin sensitivity in neuronal cells . Molecular and Cellular Endocrinology . 429 . 50–61 . July 2016 . 27040307 . 10.1016/j.mce.2016.03.035 . 34525487 .
  28. Rong R, Surace EI, Haipek CA, Gutmann DH, Ye K . Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression . Oncogene . 23 . 52 . 8447–54 . November 2004 . 15378014 . 10.1038/sj.onc.1207794 . 13480894 .
  29. Li T, Zhang J, Zhu F, Wen W, Zykova T, Li X, Liu K, Peng C, Ma W, Shi G, Dong Z, Bode AM, Dong Z . P21-activated protein kinase (PAK2)-mediated c-Jun phosphorylation at 5 threonine sites promotes cell transformation . Carcinogenesis . 32 . 5 . 659–66 . May 2011 . 21177766 . 10.1093/carcin/bgq271 . 3086698.
  30. Lee JH, Wittki S, Bräu T, Dreyer FS, Krätzel K, Dindorf J, Johnston IC, Gross S, Kremmer E, Zeidler R, Schlötzer-Schrehardt U, Lichtenheld M, Saksela K, Harrer T, Schuler G, Federico M, Baur AS . HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases . Molecular Cell . 49 . 4 . 668–79 . February 2013 . 23317503 . 10.1016/j.molcel.2012.12.004 . free .
  31. Berger A, Hoelbl-Kovacic A, Bourgeais J, Hoefling L, Warsch W, Grundschober E, Uras IZ, Menzl I, Putz EM, Hoermann G, Schuster C, Fajmann S, Leitner E, Kubicek S, Moriggl R, Gouilleux F, Sexl V . PAK-dependent STAT5 serine phosphorylation is required for BCR-ABL-induced leukemogenesis . Leukemia . 28 . 3 . 629–41 . March 2014 . 24263804 . 10.1038/leu.2013.351 . 3948164.
  32. Huang Z, Traugh JA, Bishop JM . Negative control of the Myc protein by the stress-responsive kinase Pak2 . Molecular and Cellular Biology . 24 . 4 . 1582–94 . February 2004 . 14749374 . 10.1128/mcb.24.4.1582-1594.2004 . 344192.
  33. Zeng Y, Broxmeyer HE, Staser K, Chitteti BR, Park SJ, Hahn S, Cooper S, Sun Z, Jiang L, Yang X, Yuan J, Kosoff R, Sandusky G, Srour EF, Chernoff J, Clapp DW . Pak2 regulates hematopoietic progenitor cell proliferation, survival, and differentiation . Stem Cells . 33 . 5 . 1630–41 . May 2015 . 25586960 . 10.1002/stem.1951 . 4409559.

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