PAK2_HUMAN
ID PAK2_HUMAN Reviewed; 524 AA.
AC Q13177; Q13154; Q6ISC3;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2007, sequence version 3.
DT 03-AUG-2022, entry version 225.
DE RecName: Full=Serine/threonine-protein kinase PAK 2;
DE EC=2.7.11.1;
DE AltName: Full=Gamma-PAK;
DE AltName: Full=PAK65;
DE AltName: Full=S6/H4 kinase;
DE AltName: Full=p21-activated kinase 2;
DE Short=PAK-2;
DE AltName: Full=p58;
DE Contains:
DE RecName: Full=PAK-2p27;
DE Short=p27;
DE Contains:
DE RecName: Full=PAK-2p34;
DE Short=p34;
DE AltName: Full=C-t-PAK2;
GN Name=PAK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Sells M., Knause U.J., Bagrodia S., Ambrose D., Bokoch G.M., Chernoff J.;
RL Submitted (APR-1995) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 32-524, AND PROTEIN SEQUENCE OF 401-417.
RC TISSUE=Placenta;
RX PubMed=7744004; DOI=10.1002/j.1460-2075.1995.tb07189.x;
RA Martin G.A., Bollag G., McCormick F., Abo A.;
RT "A novel serine kinase activated by rac1/CDC42Hs-dependent
RT autophosphorylation is related to PAK65 and STE20.";
RL EMBO J. 14:1970-1978(1995).
RN [4]
RP ERRATUM OF PUBMED:7744004.
RX PubMed=7556080; DOI=10.1002/j.1460-2075.1995.tb00113.x;
RA Martin G.A., Bollag G., McCormick F., Abo A.;
RL EMBO J. 14:4385-4385(1995).
RN [5]
RP AUTOPHOSPHORYLATION.
RX PubMed=7673144; DOI=10.1074/jbc.270.36.21121;
RA Benner G.E., Dennis P.B., Masaracchia R.A.;
RT "Activation of an S6/H4 kinase (PAK 65) from human placenta by
RT intramolecular and intermolecular autophosphorylation.";
RL J. Biol. Chem. 270:21121-21128(1995).
RN [6]
RP PROTEOLYTIC CLEAVAGE AT ASP-212 BY CASPASE-3, FUNCTION, AND MUTAGENESIS OF
RP ASP-212.
RX PubMed=9171063; DOI=10.1126/science.276.5318.1571;
RA Rudel T., Bokoch G.M.;
RT "Membrane and morphological changes in apoptotic cells regulated by
RT caspase-mediated activation of PAK2.";
RL Science 276:1571-1574(1997).
RN [7]
RP PROTEOLYTIC CLEAVAGE AT ASP-212 BY CASPASE-3, AUTOPHOSPHORYLATION, AND
RP MUTAGENESIS OF LYS-278 AND THR-402.
RX PubMed=9786869; DOI=10.1074/jbc.273.44.28733;
RA Walter B.N., Huang Z., Jakobi R., Tuazon P.T., Alnemri E.S., Litwack G.,
RA Traugh J.A.;
RT "Cleavage and activation of p21-activated protein kinase gamma-PAK by CPP32
RT (caspase 3). Effects of autophosphorylation on activity.";
RL J. Biol. Chem. 273:28733-28739(1998).
RN [8]
RP INTERACTION WITH HIV-1 NEF (MICROBIAL INFECTION).
RX PubMed=11070003; DOI=10.1128/jvi.74.23.11081-11087.2000;
RA Arora V.K., Molina R.P., Foster J.L., Blakemore J.L., Chernoff J.,
RA Fredericksen B.L., Garcia J.V.;
RT "Lentivirus Nef specifically activates Pak2.";
RL J. Virol. 74:11081-11087(2000).
RN [9]
RP FUNCTION (PAK-2P34), UBIQUITINATION, SUBCELLULAR LOCATION, AND MUTAGENESIS
RP OF 239-ILE--GLY-243 AND 246-LYS--LYS-248.
RX PubMed=12853446; DOI=10.1074/jbc.m306494200;
RA Jakobi R., McCarthy C.C., Koeppel M.A., Stringer D.K.;
RT "Caspase-activated PAK-2 is regulated by subcellular targeting and
RT proteasomal degradation.";
RL J. Biol. Chem. 278:38675-38685(2003).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF MKNK1.
RX PubMed=15234964; DOI=10.1074/jbc.m407337200;
RA Orton K.C., Ling J., Waskiewicz A.J., Cooper J.A., Merrick W.C.,
RA Korneeva N.L., Rhoads R.E., Sonenberg N., Traugh J.A.;
RT "Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits
RT phosphorylation and interaction of eIF4G with Mnk.";
RL J. Biol. Chem. 279:38649-38657(2004).
RN [11]
RP INTERACTION WITH ARHGAP10, AND SUBCELLULAR LOCATION.
RX PubMed=15471851; DOI=10.1074/jbc.m410530200;
RA Koeppel M.A., McCarthy C.C., Moertl E., Jakobi R.;
RT "Identification and characterization of PS-GAP as a novel regulator of
RT caspase-activated PAK-2.";
RL J. Biol. Chem. 279:53653-53664(2004).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [13]
RP INTERACTION WITH SH3MD4.
RX PubMed=16374509; DOI=10.1038/sj.embor.7400596;
RA Kaerkkaeinen S., Hiipakka M., Wang J.-H., Kleino I., Vaehae-Jaakkola M.,
RA Renkema G.H., Liss M., Wagner R., Saksela K.;
RT "Identification of preferred protein interactions by phage-display of the
RT human Src homology-3 proteome.";
RL EMBO Rep. 7:186-191(2006).
RN [14]
RP FUNCTION (PAK-2P34), MYRISTOYLATION AT GLY-213 (PAK-2P34), AND SUBCELLULAR
RP LOCATION.
RX PubMed=16617111; DOI=10.1073/pnas.0600824103;
RA Vilas G.L., Corvi M.M., Plummer G.J., Seime A.M., Lambkin G.R.,
RA Berthiaume L.G.;
RT "Posttranslational myristoylation of caspase-activated p21-activated
RT protein kinase 2 (PAK2) potentiates late apoptotic events.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:6542-6547(2006).
RN [15]
RP INTERACTION WITH SCRIB.
RX PubMed=18716323; DOI=10.1093/hmg/ddn248;
RA Nola S., Sebbagh M., Marchetto S., Osmani N., Nourry C., Audebert S.,
RA Navarro C., Rachel R., Montcouquiol M., Sans N., Etienne-Manneville S.,
RA Borg J.-P., Santoni M.-J.;
RT "Scrib regulates PAK activity during the cell migration process.";
RL Hum. Mol. Genet. 17:3552-3565(2008).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-58; SER-141 AND THR-169, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP INTERACTION WITH ARHGEF7 AND GIT1.
RX PubMed=19273597; DOI=10.1128/mcb.01713-08;
RA Mitsushima M., Toyoshima F., Nishida E.;
RT "Dual role of Cdc42 in spindle orientation control of adherent cells.";
RL Mol. Cell. Biol. 29:2816-2827(2009).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-141 AND SER-197, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [20]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-128, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [21]
RP INTERACTION WITH RAC1.
RX PubMed=20696164; DOI=10.1016/j.febslet.2010.07.060;
RA Kaerkkaeinen S., van der Linden M., Renkema G.H.;
RT "POSH2 is a RING finger E3 ligase with Rac1 binding activity through a
RT partial CRIB domain.";
RL FEBS Lett. 584:3867-3872(2010).
RN [22]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=19923322; DOI=10.1091/mbc.e09-03-0232;
RA Hsu R.M., Tsai M.H., Hsieh Y.J., Lyu P.C., Yu J.S.;
RT "Identification of MYO18A as a novel interacting partner of the
RT PAK2/betaPIX/GIT1 complex and its potential function in modulating
RT epithelial cell migration.";
RL Mol. Biol. Cell 21:287-301(2010).
RN [23]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE
RP ANALYSIS] AT SER-2 AND SER-141, CLEAVAGE OF INITIATOR METHIONINE [LARGE
RP SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP AUTOPHOSPHORYLATION.
RX PubMed=21098037; DOI=10.1074/jbc.m110.156505;
RA Wang J., Wu J.W., Wang Z.X.;
RT "Mechanistic studies of the autoactivation of PAK2: a two-step model of cis
RT initiation followed by trans amplification.";
RL J. Biol. Chem. 286:2689-2695(2011).
RN [26]
RP FUNCTION IN PHOSPHORYLATION OF MAPK4 AND MAPK6.
RX PubMed=21317288; DOI=10.1074/jbc.m110.181743;
RA De la Mota-Peynado A., Chernoff J., Beeser A.;
RT "Identification of the atypical MAPK Erk3 as a novel substrate for p21-
RT activated kinase (Pak) activity.";
RL J. Biol. Chem. 286:13603-13611(2011).
RN [27]
RP FUNCTION IN PHOSPHORYLATION OF JUN.
RX PubMed=21177766; DOI=10.1093/carcin/bgq271;
RA Li T., Zhang J., Zhu F., Wen W., Zykova T., Li X., Liu K., Peng C., Ma W.,
RA Shi G., Dong Z., Bode A.M., Dong Z.;
RT "P21-activated protein kinase (PAK2)-mediated c-Jun phosphorylation at 5
RT threonine sites promotes cell transformation.";
RL Carcinogenesis 32:659-666(2011).
RN [28]
RP FUNCTION IN PHOSPHORYLATION OF HISTONE H4.
RX PubMed=21724829; DOI=10.1101/gad.2055511;
RA Kang B., Pu M., Hu G., Wen W., Dong Z., Zhao K., Stillman B., Zhang Z.;
RT "Phosphorylation of H4 Ser 47 promotes HIRA-mediated nucleosome assembly.";
RL Genes Dev. 25:1359-1364(2011).
RN [29]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE
RP ANALYSIS] AT SER-2; SER-141 AND THR-169, CLEAVAGE OF INITIATOR METHIONINE
RP [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE
RP SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [30]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [31]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2; SER-20; SER-55; SER-58;
RP THR-60; SER-64; THR-134; SER-141; THR-143; THR-154; THR-169 AND SER-197,
RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [33]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-139 AND SER-141, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (2.86 ANGSTROMS) OF 121-136.
RX PubMed=21170023; DOI=10.1038/nature09593;
RA Selyunin A.S., Sutton S.E., Weigele B.A., Reddick L.E., Orchard R.C.,
RA Bresson S.M., Tomchick D.R., Alto N.M.;
RT "The assembly of a GTPase-kinase signalling complex by a bacterial
RT catalytic scaffold.";
RL Nature 469:107-111(2011).
CC -!- FUNCTION: Serine/threonine protein kinase that plays a role in a
CC variety of different signaling pathways including cytoskeleton
CC regulation, cell motility, cell cycle progression, apoptosis or
CC proliferation. Acts as downstream effector of the small GTPases CDC42
CC and RAC1. Activation by the binding of active CDC42 and RAC1 results in
CC a conformational change and a subsequent autophosphorylation on several
CC serine and/or threonine residues. Full-length PAK2 stimulates cell
CC survival and cell growth. Phosphorylates MAPK4 and MAPK6 and activates
CC the downstream target MAPKAPK5, a regulator of F-actin polymerization
CC and cell migration. Phosphorylates JUN and plays an important role in
CC EGF-induced cell proliferation. Phosphorylates many other substrates
CC including histone H4 to promote assembly of H3.3 and H4 into
CC nucleosomes, BAD, ribosomal protein S6, or MBP. Additionally,
CC associates with ARHGEF7 and GIT1 to perform kinase-independent
CC functions such as spindle orientation control during mitosis. On the
CC other hand, apoptotic stimuli such as DNA damage lead to caspase-
CC mediated cleavage of PAK2, generating PAK-2p34, an active p34 fragment
CC that translocates to the nucleus and promotes cellular apoptosis
CC involving the JNK signaling pathway. Caspase-activated PAK2
CC phosphorylates MKNK1 and reduces cellular translation.
CC {ECO:0000269|PubMed:12853446, ECO:0000269|PubMed:15234964,
CC ECO:0000269|PubMed:16617111, ECO:0000269|PubMed:19923322,
CC ECO:0000269|PubMed:21177766, ECO:0000269|PubMed:21317288,
CC ECO:0000269|PubMed:21724829, ECO:0000269|PubMed:9171063}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- ACTIVITY REGULATION: Activated by binding small G proteins. Binding of
CC GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers
CC from the autoinhibited dimer, enables phosphorylation of Thr-402 and
CC allows the kinase domain to adopt an active structure (By similarity).
CC Following caspase cleavage, autophosphorylated PAK-2p34 is
CC constitutively active. {ECO:0000250}.
CC -!- SUBUNIT: Interacts tightly with GTP-bound but not GDP-bound CDC42/p21
CC and RAC1. Interacts with SH3MD4. Interacts with SCRIB. Interacts with
CC ARHGEF7 and GIT1. PAK-2p34 interacts with ARHGAP10 (PubMed:15471851,
CC PubMed:16374509, PubMed:18716323, PubMed:19273597). Interacts with RAC1
CC (PubMed:20696164). {ECO:0000269|PubMed:15471851,
CC ECO:0000269|PubMed:16374509, ECO:0000269|PubMed:18716323,
CC ECO:0000269|PubMed:19273597, ECO:0000269|PubMed:20696164}.
CC -!- SUBUNIT: (Microbial infection) Interacts with and activated by HIV-1
CC Nef. {ECO:0000269|PubMed:11070003}.
CC -!- INTERACTION:
CC Q13177; Q9NYB9-2: ABI2; NbExp=3; IntAct=EBI-1045887, EBI-11096309;
CC Q13177; Q15052: ARHGEF6; NbExp=5; IntAct=EBI-1045887, EBI-1642523;
CC Q13177; Q14155: ARHGEF7; NbExp=4; IntAct=EBI-1045887, EBI-717515;
CC Q13177; P55210: CASP7; NbExp=6; IntAct=EBI-1045887, EBI-523958;
CC Q13177; P60953: CDC42; NbExp=8; IntAct=EBI-1045887, EBI-81752;
CC Q13177; P62993: GRB2; NbExp=2; IntAct=EBI-1045887, EBI-401755;
CC Q13177; P08631: HCK; NbExp=2; IntAct=EBI-1045887, EBI-346340;
CC Q13177; P42858: HTT; NbExp=2; IntAct=EBI-1045887, EBI-466029;
CC Q13177; P53667: LIMK1; NbExp=2; IntAct=EBI-1045887, EBI-444403;
CC Q13177; P16333: NCK1; NbExp=5; IntAct=EBI-1045887, EBI-389883;
CC Q13177; O43639: NCK2; NbExp=8; IntAct=EBI-1045887, EBI-713635;
CC Q13177; Q13177: PAK2; NbExp=3; IntAct=EBI-1045887, EBI-1045887;
CC Q13177; P63000: RAC1; NbExp=5; IntAct=EBI-1045887, EBI-413628;
CC Q13177; P04049: RAF1; NbExp=2; IntAct=EBI-1045887, EBI-365996;
CC Q13177; Q9H4E5: RHOJ; NbExp=6; IntAct=EBI-1045887, EBI-6285694;
CC Q13177; Q8TEJ3: SH3RF3; NbExp=2; IntAct=EBI-1045887, EBI-7975674;
CC Q13177; Q9BX66: SORBS1; NbExp=2; IntAct=EBI-1045887, EBI-433642;
CC Q13177; O94875: SORBS2; NbExp=2; IntAct=EBI-1045887, EBI-311323;
CC Q13177; O60504: SORBS3; NbExp=6; IntAct=EBI-1045887, EBI-741237;
CC Q13177; P12931: SRC; NbExp=2; IntAct=EBI-1045887, EBI-621482;
CC Q13177; O55043: Arhgef7; Xeno; NbExp=8; IntAct=EBI-1045887, EBI-3649585;
CC Q13177; Q5PP90: US3(L); Xeno; NbExp=2; IntAct=EBI-1045887, EBI-15780451;
CC -!- SUBCELLULAR LOCATION: [Serine/threonine-protein kinase PAK 2]:
CC Cytoplasm. Note=MYO18A mediates the cellular distribution of the PAK2-
CC ARHGEF7-GIT1 complex to the inner surface of the cell membrane.
CC -!- SUBCELLULAR LOCATION: [PAK-2p34]: Nucleus. Cytoplasm, perinuclear
CC region. Membrane; Lipid-anchor. Note=Interaction with ARHGAP10 probably
CC changes PAK-2p34 location to cytoplasmic perinuclear region.
CC Myristoylation changes PAK-2p34 location to the membrane.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Higher levels seen in
CC skeletal muscle, ovary, thymus and spleen.
CC -!- PTM: Full-length PAK2 is autophosphorylated when activated by
CC CDC42/p21. Following cleavage, both peptides, PAK-2p27 and PAK-2p34,
CC become highly autophosphorylated, with PAK-2p27 being phosphorylated on
CC serine and PAK-2p34 on threonine residues, respectively.
CC Autophosphorylation of PAK-2p27 can occur in the absence of any
CC effectors and is dependent on phosphorylation of Thr-402, because PAK-
CC 2p27 is acting as an exogenous substrate.
CC -!- PTM: During apoptosis proteolytically cleaved by caspase-3 or caspase-
CC 3-like proteases to yield active PAK-2p34.
CC -!- PTM: Ubiquitinated, leading to its proteasomal degradation.
CC {ECO:0000269|PubMed:12853446}.
CC -!- PTM: PAK-2p34 is myristoylated. {ECO:0000269|PubMed:16617111}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. STE20 subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PAK2ID41634ch3q29.html";
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DR EMBL; U24153; AAA65442.1; -; mRNA.
DR EMBL; BC069613; AAH69613.1; -; mRNA.
DR EMBL; U25975; AAA75468.1; -; mRNA.
DR CCDS; CCDS3321.1; -.
DR PIR; S58682; S58682.
DR RefSeq; NP_002568.2; NM_002577.4.
DR RefSeq; XP_011511172.1; XM_011512870.2.
DR RefSeq; XP_016861990.1; XM_017006501.1.
DR PDB; 3PCS; X-ray; 2.86 A; E/F/G/H=121-136.
DR PDBsum; 3PCS; -.
DR AlphaFoldDB; Q13177; -.
DR SMR; Q13177; -.
DR BioGRID; 111098; 147.
DR DIP; DIP-38249N; -.
DR ELM; Q13177; -.
DR IntAct; Q13177; 70.
DR MINT; Q13177; -.
DR STRING; 9606.ENSP00000314067; -.
DR BindingDB; Q13177; -.
DR ChEMBL; CHEMBL4487; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; Q13177; -.
DR GuidetoPHARMACOLOGY; 2134; -.
DR GlyGen; Q13177; 3 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; Q13177; -.
DR MetOSite; Q13177; -.
DR PhosphoSitePlus; Q13177; -.
DR SwissPalm; Q13177; -.
DR BioMuta; PAK2; -.
DR DMDM; 143811432; -.
DR OGP; Q13177; -.
DR CPTAC; CPTAC-1628; -.
DR CPTAC; CPTAC-1726; -.
DR EPD; Q13177; -.
DR jPOST; Q13177; -.
DR MassIVE; Q13177; -.
DR MaxQB; Q13177; -.
DR PaxDb; Q13177; -.
DR PeptideAtlas; Q13177; -.
DR PRIDE; Q13177; -.
DR ProteomicsDB; 59208; -.
DR Antibodypedia; 3583; 873 antibodies from 43 providers.
DR DNASU; 5062; -.
DR Ensembl; ENST00000327134.7; ENSP00000314067.3; ENSG00000180370.10.
DR GeneID; 5062; -.
DR KEGG; hsa:5062; -.
DR MANE-Select; ENST00000327134.7; ENSP00000314067.3; NM_002577.4; NP_002568.2.
DR UCSC; uc003fwy.4; human.
DR CTD; 5062; -.
DR DisGeNET; 5062; -.
DR GeneCards; PAK2; -.
DR HGNC; HGNC:8591; PAK2.
DR HPA; ENSG00000180370; Low tissue specificity.
DR MIM; 605022; gene.
DR neXtProt; NX_Q13177; -.
DR OpenTargets; ENSG00000180370; -.
DR PharmGKB; PA32918; -.
DR VEuPathDB; HostDB:ENSG00000180370; -.
DR eggNOG; KOG0578; Eukaryota.
DR GeneTree; ENSGT00950000182988; -.
DR HOGENOM; CLU_000288_26_6_1; -.
DR InParanoid; Q13177; -.
DR OMA; IMMMEMA; -.
DR OrthoDB; 757766at2759; -.
DR PhylomeDB; Q13177; -.
DR TreeFam; TF105351; -.
DR BRENDA; 2.7.11.1; 2681.
DR PathwayCommons; Q13177; -.
DR Reactome; R-HSA-164944; Nef and signal transduction.
DR Reactome; R-HSA-202433; Generation of second messenger molecules.
DR Reactome; R-HSA-211728; Regulation of PAK-2p34 activity by PS-GAP/RHG10.
DR Reactome; R-HSA-211733; Regulation of activated PAK-2p34 by proteasome mediated degradation.
DR Reactome; R-HSA-211736; Stimulation of the cell death response by PAK-2p34.
DR Reactome; R-HSA-2871796; FCERI mediated MAPK activation.
DR Reactome; R-HSA-389359; CD28 dependent Vav1 pathway.
DR Reactome; R-HSA-3928664; Ephrin signaling.
DR Reactome; R-HSA-399954; Sema3A PAK dependent Axon repulsion.
DR Reactome; R-HSA-428540; Activation of RAC1.
DR Reactome; R-HSA-4420097; VEGFA-VEGFR2 Pathway.
DR Reactome; R-HSA-445355; Smooth Muscle Contraction.
DR Reactome; R-HSA-5218920; VEGFR2 mediated vascular permeability.
DR Reactome; R-HSA-5621575; CD209 (DC-SIGN) signaling.
DR Reactome; R-HSA-5627123; RHO GTPases activate PAKs.
DR Reactome; R-HSA-5687128; MAPK6/MAPK4 signaling.
DR Reactome; R-HSA-8950505; Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation.
DR Reactome; R-HSA-9013148; CDC42 GTPase cycle.
DR Reactome; R-HSA-9013149; RAC1 GTPase cycle.
DR Reactome; R-HSA-9013404; RAC2 GTPase cycle.
DR Reactome; R-HSA-9013406; RHOQ GTPase cycle.
DR Reactome; R-HSA-9013407; RHOH GTPase cycle.
DR Reactome; R-HSA-9013408; RHOG GTPase cycle.
DR Reactome; R-HSA-9013409; RHOJ GTPase cycle.
DR Reactome; R-HSA-9013420; RHOU GTPase cycle.
DR Reactome; R-HSA-9013423; RAC3 GTPase cycle.
DR Reactome; R-HSA-9013424; RHOV GTPase cycle.
DR SignaLink; Q13177; -.
DR SIGNOR; Q13177; -.
DR BioGRID-ORCS; 5062; 106 hits in 1117 CRISPR screens.
DR ChiTaRS; PAK2; human.
DR EvolutionaryTrace; Q13177; -.
DR GeneWiki; PAK2; -.
DR GenomeRNAi; 5062; -.
DR Pharos; Q13177; Tchem.
DR PRO; PR:Q13177; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q13177; protein.
DR Bgee; ENSG00000180370; Expressed in ganglionic eminence and 208 other tissues.
DR ExpressionAtlas; Q13177; baseline and differential.
DR Genevisible; Q13177; HS.
DR GO; GO:0005911; C:cell-cell junction; IMP:ARUK-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005829; C:cytosol; IDA:CAFA.
DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0014069; C:postsynaptic density; IEA:Ensembl.
DR GO; GO:0030141; C:secretory granule; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc.
DR GO; GO:0019901; F:protein kinase binding; IPI:BHF-UCL.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL.
DR GO; GO:0030296; F:protein tyrosine kinase activator activity; IDA:BHF-UCL.
DR GO; GO:0031267; F:small GTPase binding; IPI:CAFA.
DR GO; GO:0034333; P:adherens junction assembly; IMP:ARUK-UCL.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0070830; P:bicellular tight junction assembly; IMP:ARUK-UCL.
DR GO; GO:0003300; P:cardiac muscle hypertrophy; IEA:Ensembl.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0071560; P:cellular response to transforming growth factor beta stimulus; IEA:Ensembl.
DR GO; GO:0060996; P:dendritic spine development; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:2001271; P:negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis; IDA:UniProtKB.
DR GO; GO:0006469; P:negative regulation of protein kinase activity; TAS:ProtInc.
DR GO; GO:0051497; P:negative regulation of stress fiber assembly; IMP:ARUK-UCL.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0016310; P:phosphorylation; IDA:UniProtKB.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:MGI.
DR GO; GO:0150105; P:protein localization to cell-cell junction; IMP:ARUK-UCL.
DR GO; GO:0006468; P:protein phosphorylation; IDA:MGI.
DR GO; GO:0050770; P:regulation of axonogenesis; IBA:GO_Central.
DR GO; GO:0051493; P:regulation of cytoskeleton organization; IMP:ARUK-UCL.
DR GO; GO:0040008; P:regulation of growth; IEA:UniProtKB-KW.
DR GO; GO:0043408; P:regulation of MAPK cascade; IBA:GO_Central.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0002223; P:stimulatory C-type lectin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; TAS:Reactome.
DR CDD; cd01093; CRIB_PAK_like; 1.
DR CDD; cd06655; STKc_PAK2; 1.
DR Gene3D; 3.90.810.10; -; 1.
DR IDEAL; IID00244; -.
DR InterPro; IPR000095; CRIB_dom.
DR InterPro; IPR036936; CRIB_dom_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR035065; PAK2.
DR InterPro; IPR033923; PAK_BD.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR035064; STK_PAK2.
DR PANTHER; PTHR45832:SF1; PTHR45832:SF1; 1.
DR Pfam; PF00786; PBD; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00285; PBD; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50108; CRIB; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Allosteric enzyme; Apoptosis; ATP-binding;
KW Cytoplasm; Direct protein sequencing; Growth regulation;
KW Host-virus interaction; Kinase; Lipoprotein; Membrane; Myristate;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:22223895,
FT ECO:0007744|PubMed:22814378"
FT CHAIN 2..524
FT /note="Serine/threonine-protein kinase PAK 2"
FT /id="PRO_0000086465"
FT CHAIN 2..212
FT /note="PAK-2p27"
FT /id="PRO_0000304922"
FT CHAIN 213..524
FT /note="PAK-2p34"
FT /id="PRO_0000304923"
FT DOMAIN 74..87
FT /note="CRIB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00057"
FT DOMAIN 249..499
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..81
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 69..137
FT /note="Autoregulatory region"
FT /evidence="ECO:0000250"
FT REGION 69..112
FT /note="GTPase-binding"
FT /evidence="ECO:0000250"
FT REGION 143..164
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 169..188
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 245..251
FT /note="Nuclear localization signal"
FT COMPBIAS 41..78
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 367
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 255..263
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 278
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 212..213
FT /note="Cleavage; by caspase-3 or caspase-3-like proteases"
FT /evidence="ECO:0000269|PubMed:9171063,
FT ECO:0000269|PubMed:9786869"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:22223895,
FT ECO:0007744|PubMed:22814378"
FT MOD_RES 2
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 20
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 55
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 58
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 60
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 62
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8CIN4"
FT MOD_RES 64
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 128
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 134
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 139
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 141
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 143
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 152
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8CIN4"
FT MOD_RES 154
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 169
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 197
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 402
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000305"
FT LIPID 213
FT /note="N-myristoyl glycine; in form PAK-2p34"
FT /evidence="ECO:0000269|PubMed:16617111"
FT MUTAGEN 212
FT /note="D->N: Inhibits caspase-mediated cleavage."
FT /evidence="ECO:0000269|PubMed:9171063"
FT MUTAGEN 213
FT /note="G->A: Abolishes myristoylation of PAK-2p34 and
FT membrane location."
FT MUTAGEN 239..243
FT /note="IVSIG->REGRS: Abolishes nuclear export."
FT /evidence="ECO:0000269|PubMed:12853446"
FT MUTAGEN 246..248
FT /note="KKK->MHE: Greatly inhibits nuclear localization."
FT /evidence="ECO:0000269|PubMed:12853446"
FT MUTAGEN 278
FT /note="K->R: Abolishes kinase activity and
FT autophosphorylation."
FT /evidence="ECO:0000269|PubMed:9786869"
FT MUTAGEN 402
FT /note="T->A: Abolishes kinase activity and greatly inhibits
FT autophosphorylation of PAK-2p27 and PAK-2p34."
FT /evidence="ECO:0000269|PubMed:9786869"
FT CONFLICT 90
FT /note="A -> T (in Ref. 3; AAA75468)"
FT /evidence="ECO:0000305"
FT CONFLICT 150
FT /note="F -> L (in Ref. 1; AAA65442)"
FT /evidence="ECO:0000305"
FT CONFLICT 225
FT /note="T -> P (in Ref. 1; AAA65442)"
FT /evidence="ECO:0000305"
FT CONFLICT 258
FT /note="G -> R (in Ref. 2; AAH69613)"
FT /evidence="ECO:0000305"
FT CONFLICT 329
FT /note="G -> R (in Ref. 3; AAA75468)"
FT /evidence="ECO:0000305"
FT CONFLICT 338
FT /note="T -> TA (in Ref. 1; AAA65442)"
FT /evidence="ECO:0000305"
FT HELIX 123..126
FT /evidence="ECO:0007829|PDB:3PCS"
SQ SEQUENCE 524 AA; 58043 MW; 00A7CD15F93D4180 CRC64;
MSDNGELEDK PPAPPVRMSS TIFSTGGKDP LSANHSLKPL PSVPEEKKPR HKIISIFSGT
EKGSKKKEKE RPEISPPSDF EHTIHVGFDA VTGEFTGMPE QWARLLQTSN ITKLEQKKNP
QAVLDVLKFY DSNTVKQKYL SFTPPEKDGF PSGTPALNAK GTEAPAVVTE EEDDDEETAP
PVIAPRPDHT KSIYTRSVID PVPAPVGDSH VDGAAKSLDK QKKKTKMTDE EIMEKLRTIV
SIGDPKKKYT RYEKIGQGAS GTVFTATDVA LGQEVAIKQI NLQKQPKKEL IINEILVMKE
LKNPNIVNFL DSYLVGDELF VVMEYLAGGS LTDVVTETCM DEAQIAAVCR ECLQALEFLH
ANQVIHRDIK SDNVLLGMEG SVKLTDFGFC AQITPEQSKR STMVGTPYWM APEVVTRKAY
GPKVDIWSLG IMAIEMVEGE PPYLNENPLR ALYLIATNGT PELQNPEKLS PIFRDFLNRC
LEMDVEKRGS AKELLQHPFL KLAKPLSSLT PLIMAAKEAM KSNR
