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Gene Review

PAK2  -  p21 protein (Cdc42/Rac)-activated kinase 2

Homo sapiens

Synonyms: Gamma-PAK, PAK-2, PAK65, PAKgamma, S6/H4 kinase, ...
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Disease relevance of PAK2

  • Contrary to the current literature, Pak1 depletion strongly inhibited HIV infection in multiple cell systems and decreased levels of integrated provirus, while Pak2 depletion showed no effect [1].
  • A well conserved feature of human immunodeficiency virus, type 1 (HIV-1) and simian immunodeficiency virus (SIV) Nef is the interaction with and activation of the human p21-activated kinase 2 (PAK2) [2].
  • In conclusion, we show for the first time the activation of PAK-2 in 1-LN prostate cancer cells by a proteinase inhibitor, alpha2-macroglobulin [3].
  • Lentivirus Nef specifically activates Pak2 [4].
  • Previously we showed that UV irradiation can activate caspase-3, and the subsequent cleavage and activation of p21(Cdc42/Rac)-activated kinase 2 (PAK2) in human epidermoid carcinoma A431 cells [5].

High impact information on PAK2


Chemical compound and disease context of PAK2


Biological context of PAK2


Anatomical context of PAK2


Associations of PAK2 with chemical compounds

  • PAK2 became tyrosine phosphorylated in its N-terminal regulatory domain, where Y130 was identified as the major phosphoacceptor site [11].
  • PAK2 catalyzes MLCK phosphorylation on serine residues 439 and 991 [20].
  • We directly demonstrate that PAK2 phosphorylation impairs merlin N-term/C-term binding in vitro and in vivo [21].
  • During the activation process, auto-kinase autophosphorylates mainly on a single threonine residue Thr402 (according to the sequence numbering of human PAK2) [12].
  • Both PDT-induced caspase-3 activation and PAK2 cleavage/activation can be inhibited by the singlet oxygen scavengers, L-histidine and alpha-tocopherol, but not the hydroxyl radical scavenger, mannitol, demonstrating that singlet oxygen is an immediate early-apoptotic signal generated by PDT [22].

Physical interactions of PAK2

  • Besides showing potentially important new SH3-directed interactions, these studies also led to the discovery of novel signalling proteins, such as the PAK2-binding adaptor protein POSH2 and the ADAM15-binding sorting nexin family member SNX30 [23].

Enzymatic interactions of PAK2

  • In vitro, CPP32 cleaves recombinant gamma-PAK into two peptides; 1-212 contains the majority of the regulatory domain whereas 213-524 contains 34 amino acids of the regulatory domain plus the entire catalytic domain [24].

Regulatory relationships of PAK2

  • Collectively, the results demonstrate that cleavage and activation of PAK2 can be induced during the early stages of UV irradiation-triggered apoptosis and indicate the involvement of CPP32/caspase-3 in this process [25].
  • We determined that TGF-beta receptor signaling activates the STE20 homolog PAK2 in mammalian cells [26].
  • Cleavage and activation of p21-activated protein kinase gamma-PAK by CPP32 (caspase 3). Effects of autophosphorylation on activity [24].
  • Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK [3].
  • RNA interference releases Pak2-induced inhibition of translation in contact-inhibited cells by 2.7-fold. eIF4G mutants of the Pak2 site show that S896D inhibits translation, while S896A has no effect [27].

Other interactions of PAK2

  • Messenger RNAs for p21-activated protein kinase isoforms (PAK1, PAK2, and PAK3) were detectable in both nonpregnant and pregnant human myometrial tissue [28].
  • These data are consistent with a model in which hPAK65 functions as an effector molecule for rac1 and CDC42Hs [29].
  • We also generated a GFP-fused PAK2 truncation lacking the Cdc42/Rac interactive binding region domain, GFP-PAK2(83-149) [30].
  • The PAK2 truncation, PAK2DeltaL, blocked Ag receptor-induced NFAT activation and TCR-mediated calcium flux in Jurkat T cells [30].
  • Steady-state kinetic analysis of the initial reaction velocity of PAK2 phosphorylation of MBP is consistent with both randomly and compulsorily ordered mechanisms [31].

Analytical, diagnostic and therapeutic context of PAK2


  1. "UnPAKing" human immunodeficiency virus (HIV) replication: using small interfering RNA screening to identify novel cofactors and elucidate the role of group I PAKs in HIV infection. Nguyen, D.G., Wolff, K.C., Yin, H., Caldwell, J.S., Kuhen, K.L. J. Virol. (2006) [Pubmed]
  2. Activation of p21-activated kinase 2 and its association with Nef are conserved in murine cells but are not sufficient to induce an AIDS-like disease in CD4C/HIV transgenic mice. Vincent, P., Priceputu, E., Kay, D., Saksela, K., Jolicoeur, P., Hanna, Z. J. Biol. Chem. (2006) [Pubmed]
  3. Binding of activated alpha2-macroglobulin to its cell surface receptor GRP78 in 1-LN prostate cancer cells regulates PAK-2-dependent activation of LIMK. Misra, U.K., Deedwania, R., Pizzo, S.V. J. Biol. Chem. (2005) [Pubmed]
  4. Lentivirus Nef specifically activates Pak2. Arora, V.K., Molina, R.P., Foster, J.L., Blakemore, J.L., Chernoff, J., Fredericksen, B.L., Garcia, J.V. J. Virol. (2000) [Pubmed]
  5. Curcumin inhibits UV irradiation-induced oxidative stress and apoptotic biochemical changes in human epidermoid carcinoma A431 cells. Chan, W.H., Wu, C.C., Yu, J.S. J. Cell. Biochem. (2003) [Pubmed]
  6. Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Rudel, T., Bokoch, G.M. Science (1997) [Pubmed]
  7. The modulation of CD40 ligand signaling by transmembrane CD28 splice variant in human T cells. Mikolajczak, S.A., Ma, B.Y., Yoshida, T., Yoshida, R., Kelvin, D.J., Ochi, A. J. Exp. Med. (2004) [Pubmed]
  8. Caspases are activated in a branched protease cascade and control distinct downstream processes in Fas-induced apoptosis. Hirata, H., Takahashi, A., Kobayashi, S., Yonehara, S., Sawai, H., Okazaki, T., Yamamoto, K., Sasada, M. J. Exp. Med. (1998) [Pubmed]
  9. Activation of p21-activated kinase 2 by human immunodeficiency virus type 1 Nef induces merlin phosphorylation. Wei, B.L., Arora, V.K., Raney, A., Kuo, L.S., Xiao, G.H., O'Neill, E., Testa, J.R., Foster, J.L., Garcia, J.V. J. Virol. (2005) [Pubmed]
  10. Specific and distinct determinants mediate membrane binding and lipid raft incorporation of HIV-1(SF2) Nef. Giese, S.I., Woerz, I., Homann, S., Tibroni, N., Geyer, M., Fackler, O.T. Virology (2006) [Pubmed]
  11. Cdc42/Rac1-mediated activation primes PAK2 for superactivation by tyrosine phosphorylation. Renkema, G.H., Pulkkinen, K., Saksela, K. Mol. Cell. Biol. (2002) [Pubmed]
  12. Identification of the regulatory autophosphorylation site of autophosphorylation-dependent protein kinase (auto-kinase). Evidence that auto-kinase belongs to a member of the p21-activated kinase family. Yu, J.S., Chen, W.J., Ni, M.H., Chan, W.H., Yang, S.D. Biochem. J. (1998) [Pubmed]
  13. Heat shock stress induces cleavage and activation of PAK2 in apoptotic cells. Chan, W.H., Yu, J.S., Yang, S.D. J. Protein Chem. (1998) [Pubmed]
  14. Crystal structure of the SH3 domain of betaPIX in complex with a high affinity peptide from PAK2. Hoelz, A., Janz, J.M., Lawrie, S.D., Corwin, B., Lee, A., Sakmar, T.P. J. Mol. Biol. (2006) [Pubmed]
  15. p21-activated kinase (PAK) is required for Fas-induced JNK activation in Jurkat cells. Rudel, T., Zenke, F.T., Chuang, T.H., Bokoch, G.M. J. Immunol. (1998) [Pubmed]
  16. Cytostatic p21 G protein-activated protein kinase gamma-PAK. Roig, J., Traugh, J.A. Vitam. Horm. (2001) [Pubmed]
  17. Phosphorylation of p85 beta PIX, a Rac/Cdc42-specific guanine nucleotide exchange factor, via the Ras/ERK/PAK2 pathway is required for basic fibroblast growth factor-induced neurite outgrowth. Shin, E.Y., Shin, K.S., Lee, C.S., Woo, K.N., Quan, S.H., Soung, N.K., Kim, Y.G., Cha, C.I., Kim, S.R., Park, D., Bokoch, G.M., Kim, E.G. J. Biol. Chem. (2002) [Pubmed]
  18. p21-activated protein kinase gamma-PAK is activated by ionizing radiation and other DNA-damaging agents. Similarities and differences to alpha-PAK. Roig, J., Traugh, J.A. J. Biol. Chem. (1999) [Pubmed]
  19. Reconstitution and molecular analysis of an active human immunodeficiency virus type 1 Nef/p21-activated kinase 2 complex. Raney, A., Kuo, L.S., Baugh, L.L., Foster, J.L., Garcia, J.V. J. Virol. (2005) [Pubmed]
  20. Phosphorylation of myosin light chain kinase by p21-activated kinase PAK2. Goeckeler, Z.M., Masaracchia, R.A., Zeng, Q., Chew, T.L., Gallagher, P., Wysolmerski, R.B. J. Biol. Chem. (2000) [Pubmed]
  21. Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression. Rong, R., Surace, E.I., Haipek, C.A., Gutmann, D.H., Ye, K. Oncogene (2004) [Pubmed]
  22. Apoptotic signalling cascade in photosensitized human epidermal carcinoma A431 cells: involvement of singlet oxygen, c-Jun N-terminal kinase, caspase-3 and p21-activated kinase 2. Chan, W.H., Yu, J.S., Yang, S.D. Biochem. J. (2000) [Pubmed]
  23. Identification of preferred protein interactions by phage-display of the human Src homology-3 proteome. Kärkkäinen, S., Hiipakka, M., Wang, J.H., Kleino, I., Vähä-Jaakkola, M., Renkema, G.H., Liss, M., Wagner, R., Saksela, K. EMBO Rep. (2006) [Pubmed]
  24. Cleavage and activation of p21-activated protein kinase gamma-PAK by CPP32 (caspase 3). Effects of autophosphorylation on activity. Walter, B.N., Huang, Z., Jakobi, R., Tuazon, P.T., Alnemri, E.S., Litwack, G., Traugh, J.A. J. Biol. Chem. (1998) [Pubmed]
  25. Proteolytic cleavage and activation of PAK2 during UV irradiation-induced apoptosis in A431 cells. Tang, T.K., Chang, W.C., Chan, W.H., Yang, S.D., Ni, M.H., Yu, J.S. J. Cell. Biochem. (1998) [Pubmed]
  26. Cell-type-specific activation of PAK2 by transforming growth factor beta independent of Smad2 and Smad3. Wilkes, M.C., Murphy, S.J., Garamszegi, N., Leof, E.B. Mol. Cell. Biol. (2003) [Pubmed]
  27. Inhibition of cap-dependent translation via phosphorylation of eIF4G by protein kinase Pak2. Ling, J., Morley, S.J., Traugh, J.A. EMBO J. (2005) [Pubmed]
  28. Up-regulation of p21- and RhoA-activated protein kinases in human pregnant myometrium. Moore, F., Da Silva, C., Wilde, J.I., Smarason, A., Watson, S.P., López Bernal, A. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  29. A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20. Martin, G.A., Bollag, G., McCormick, F., Abo, A. EMBO J. (1995) [Pubmed]
  30. A novel role for p21-activated protein kinase 2 in T cell activation. Chu, P.C., Wu, J., Liao, X.C., Pardo, J., Zhao, H., Li, C., Mendenhall, M.K., Pali, E., Shen, M., Yu, S., Taylor, V.C., Aversa, G., Molineaux, S., Payan, D.G., Masuda, E.S. J. Immunol. (2004) [Pubmed]
  31. Evaluation of the catalytic mechanism of the p21-activated protein kinase PAK2. Wu, H., Zheng, Y., Wang, Z.X. Biochemistry (2003) [Pubmed]
  32. Atypical recognition consensus of CIN85/SETA/Ruk SH3 domains revealed by target-assisted iterative screening. Kurakin, A.V., Wu, S., Bredesen, D.E. J. Biol. Chem. (2003) [Pubmed]
  33. Activation of hPAK65 by caspase cleavage induces some of the morphological and biochemical changes of apoptosis. Lee, N., MacDonald, H., Reinhard, C., Halenbeck, R., Roulston, A., Shi, T., Williams, L.T. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  34. Multisite autophosphorylation of p21-activated protein kinase gamma-PAK as a function of activation. Gatti, A., Huang, Z., Tuazon, P.T., Traugh, J.A. J. Biol. Chem. (1999) [Pubmed]
  35. Isolation and characterization of a structural homologue of human PRK2 from rat liver. Distinguishing substrate and lipid activator specificities. Yu, W., Liu, J., Morrice, N.A., Wettenhall, R.E. J. Biol. Chem. (1997) [Pubmed]
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