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UniProtKB/Swiss-Prot entry Q13177

[Entry info] [Name and origin] [References] [Comments] [Cross-references] [Keywords] [Features] [Sequence] [Tools]

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Entry information
Entry name PAK2_HUMAN
Primary accession number Q13177
Secondary accession numbers Q13154 Q6ISC3
Integrated into Swiss-Prot on November 1, 1997
Sequence was last modified on April 3, 2007 (Sequence version 3)
Annotations were last modified on    June 16, 2009 (Entry version 100)
Name and origin of the protein
Protein name Serine/threonine-protein kinase PAK 2
Synonyms EC 2.7.11.1
p21-activated kinase 2
PAK-2
Gamma-PAK
PAK65
S6/H4 kinase
p58
Contains PAK-2p27
     (p27)
PAK-2p34
     (p34)
     (C-t-PAK2)
Gene name
Name: PAK2
From
Homo sapiens (Human) [TaxID: 9606] 
Taxonomy Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.
Protein existence 1: Evidence at protein level;
References
[1]
 NUCLEOTIDE SEQUENCE [MRNA].
Sells M., Knause U.J., Bagrodia S., Ambrose D., Bokoch G.M., Chernoff J.;
Submitted (APR-1995) to the EMBL/GenBank/DDBJ databases.
[2]
 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan]
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[3]
 NUCLEOTIDE SEQUENCE [MRNA] OF 32-524, AND PROTEIN SEQUENCE OF 401-417.
TISSUE=Placenta;
PubMed=7744004 [NCBI, ExPASy, EBI, Israel, Japan]
Martin G.A., Bollag G., McCormick F., Abo A.;
"A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20.";
EMBO J. 14:1970-1978(1995).
[4]
 ERRATUM.
PubMed=7556080 [NCBI, ExPASy, EBI, Israel, Japan]
Martin G.A., Bollag G., McCormick F., Abo A.;
EMBO J. 14:4385-4385(1995).
[5]
 AUTOPHOSPHORYLATION.
DOI=10.1074/jbc.270.36.21121; PubMed=7673144 [NCBI, ExPASy, EBI, Israel, Japan]
Benner G.E., Dennis P.B., Masaracchia R.A.;
"Activation of an S6/H4 kinase (PAK 65) from human placenta by intramolecular and intermolecular autophosphorylation.";
J. Biol. Chem. 270:21121-21128(1995).
[6]
 CASPASE-3 CLEAVAGE AT ASP-512, FUNCTION, AND MUTAGENESIS OF ASP-212.
DOI=10.1126/science.276.5318.1571; PubMed=9171063 [NCBI, ExPASy, EBI, Israel, Japan]
Rudel T., Bokoch G.M.;
"Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2.";
Science 276:1571-1574(1997).
[7]
 CASPASE-3 CLEAVAGE AT ASP-512, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF LYS-278 AND THR-402.
DOI=10.1074/jbc.273.44.28733; PubMed=9786869 [NCBI, ExPASy, EBI, Israel, Japan]
Walter B.N., Huang Z., Jakobi R., Tuazon P.T., Alnemri E.S., Litwack G., Traugh J.A.;
"Cleavage and activation of p21-activated protein kinase gamma-PAK by CPP32 (caspase 3). Effects of autophosphorylation on activity.";
J. Biol. Chem. 273:28733-28739(1998).
[8]
 INTERACTION WITH HIV-1 NEF.
DOI=10.1128/JVI.74.23.11081-11087.2000; PubMed=11070003 [NCBI, ExPASy, EBI, Israel, Japan]
Arora V.K., Molina R.P., Foster J.L., Blakemore J.L., Chernoff J., Fredericksen B.L., Garcia J.V.;
"Lentivirus Nef specifically activates Pak2.";
J. Virol. 74:11081-11087(2000).
[9]
 FUNCTION (PAK-2P34), UBIQUITINATION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 239-ILE--GLY-243 AND 246-LYS--LYS-248.
DOI=10.1074/jbc.M306494200; PubMed=12853446 [NCBI, ExPASy, EBI, Israel, Japan]
Jakobi R., McCarthy C.C., Koeppel M.A., Stringer D.K.;
"Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation.";
J. Biol. Chem. 278:38675-38685(2003).
[10]
 INTERACTION WITH ARHGAP10, AND SUBCELLULAR LOCATION.
DOI=10.1074/jbc.M410530200; PubMed=15471851 [NCBI, ExPASy, EBI, Israel, Japan]
Koeppel M.A., McCarthy C.C., Moertl E., Jakobi R.;
"Identification and characterization of PS-GAP as a novel regulator of caspase-activated PAK-2.";
J. Biol. Chem. 279:53653-53664(2004).
[11]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2; SER-141 AND THR-143, AND MASS SPECTROMETRY.
TISSUE=Epithelium;
DOI=10.1016/j.cell.2006.09.026; PubMed=17081983 [NCBI, ExPASy, EBI, Israel, Japan]
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.";
Cell 127:635-648(2006).
[12]
 INTERACTION WITH SH3MD4.
DOI=10.1038/sj.embor.7400596; PubMed=16374509 [NCBI, ExPASy, EBI, Israel, Japan]
Kaerkkaeinen S., Hiipakka M., Wang J.-H., Kleino I., Vaehae-Jaakkola M., Renkema G.H., Liss M., Wagner R., Saksela K.;
"Identification of preferred protein interactions by phage-display of the human Src homology-3 proteome.";
EMBO Rep. 7:186-191(2006).
[13]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-141, AND MASS SPECTROMETRY.
TISSUE=Epithelium;
DOI=10.1038/nbt1240; PubMed=16964243 [NCBI, ExPASy, EBI, Israel, Japan]
Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
"A probability-based approach for high-throughput protein phosphorylation analysis and site localization.";
Nat. Biotechnol. 24:1285-1292(2006).
[14]
 FUNCTION (PAK-2P34), MYRISTOYLATION AT GLY-213 (PAK-2P34), AND SUBCELLULAR LOCATION.
DOI=10.1073/pnas.0600824103; PubMed=16617111 [NCBI, ExPASy, EBI, Israel, Japan]
Vilas G.L., Corvi M.M., Plummer G.J., Seime A.M., Lambkin G.R., Berthiaume L.G.;
"Posttranslational myristoylation of caspase-activated p21-activated protein kinase 2 (PAK2) potentiates late apoptotic events.";
Proc. Natl. Acad. Sci. U.S.A. 103:6542-6547(2006).
[15]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-60, AND MASS SPECTROMETRY.
TISSUE=Platelet;
DOI=10.1021/pr0704130; PubMed=18088087 [NCBI, ExPASy, EBI, Israel, Japan]
Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A.;
"Phosphoproteome of resting human platelets.";
J. Proteome Res. 7:526-534(2008).
[16]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-58; SER-141 AND THR-169, AND MASS SPECTROMETRY.
DOI=10.1073/pnas.0805139105; PubMed=18669648 [NCBI, ExPASy, EBI, Israel, Japan]
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.;
"A quantitative atlas of mitotic phosphorylation.";
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
[17]
 IDENTIFICATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
Colinge J., Superti-Furga G., Bennett K.L.;
Submitted (OCT-2008) to UniProtKB.
Comments
  • FUNCTION: The activated kinase acts on a variety of targets. Phosphorylates ribosomal protein S6, histone H4 and myelin basic protein. Full length PAK 2 stimulates cell survival and cell growth. The process is, at least in part, mediated by phosphorylation and inhibition of pro-apoptotic BAD. Caspase-activated PAK-2p34 is involved in cell death response, probably involving the JNK signaling pathway. Cleaved PAK-2p34 seems to have a higher activity than the CDC42-activated form.
  • CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
  • ENZYME REGULATION: Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-402 and allows the kinase domain to adopt an active structure (By similarity). Following caspase cleavage, autophosphorylted PAK-2p34 is constitutively active.
  • SUBUNIT: Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Interacts with SH3MD4. Interacts with and activated by HIV-1 Nef. PAK-2p34 interacts with ARHGAP10.
  • INTERACTION:
    Self; NbExp=2; IntAct=EBI-1045887, EBI-1045887;
    Q9Y2X7:GIT1; NbExp=1; IntAct=EBI-1045887, EBI-466061;
    Q14161:GIT2; NbExp=1; IntAct=EBI-1045887, EBI-1046878;
    P53667:LIMK1; NbExp=2; IntAct=EBI-1045887, EBI-444403;
    P25205:MCM3; NbExp=1; IntAct=EBI-1045887, EBI-355153;
    P35580:MYH10; NbExp=1; IntAct=EBI-1045887, EBI-351758;
    P04049:RAF1; NbExp=2; IntAct=EBI-1045887, EBI-365996;
  • SUBCELLULAR LOCATION: Serine/threonine-protein kinase PAK 2: Cytoplasm.
  • SUBCELLULAR LOCATION: PAK-2p34: Nucleus. Cytoplasm, perinuclear region. Membrane; Lipid-anchor. Note=Interaction with ARHGAP10 probably changes PAK-2p34 location to cytoplasmic perinuclear region. Myristoylation changes PAK-2p34 location to the membrane.
  • TISSUE SPECIFICITY: Ubiquitously expressed. Higher levels seen in skeletal muscle, ovary, thymus and spleen.
  • PTM: Full length PAK 2 is autophosphorylated when activated by CDC42/p21. Following cleavage, both peptides, PAK-2p27 and PAK-2p34, become highly autophosphorylated, with PAK-2p27 being phosphorylated on serine and PAK-2p34 on threonine residues, respectively. Autophosphorylation of PAK-2p27 can occur in the absence of any effectors and is dependent on phosphorylation of Thr-402, because PAK-2p27 is acting as an exogenous substrate.
  • PTM: During apoptosis proteolytically cleaved by caspase-3 or caspase-3-like proteases to yield active PAK-2p34.
  • PTM: Ubiquitinated, leading to its proteosomal degradation.
  • PTM: PAK-2p34 is myristoylated.
  • SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.
  • SIMILARITY: Contains 1 CRIB domain.
  • SIMILARITY: Contains 1 protein kinase domain.
Copyright
Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.
Cross-references
Sequence databases
EMBL
U24153; AAA65442.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
BC069613; AAH69613.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
U25975; AAA75468.1; -; mRNA.[EMBL / GenBank / DDBJ] [CoDingSequence]
IPI IPI00419979; -.
PIR S58682; S58682.
RefSeq NP_002568.2; -.
UniGene Hs.518530
3D structure databases
HSSP Q13153; 1F3M. [HSSP ENTRY / PDB]
SMR Q13177; 77-143, 228-519.
ModBase Q13177.
Protein-protein interaction databases
IntAct Q13177; 47.
PTM databases
PhosphoSite Q13177; -.
Enzyme and pathway databases
BRENDA 2.7.11.1; 247.
Pathway_Interaction_DB faspathway; FAS signaling pathway (CD95).
fcer1pathway; Fc-epsilon receptor I signaling in mast cells.
p38alphabetapathway; Regulation of p38-alpha and p38-beta.
Reactome REACT_578; Apoptosis.
REACT_6185; HIV Infection.
2D gel databases
OGP Q13177; -.
Organism-specific databases
GeneCards GC03P197955; -.
H-InvDB HIX0030815; -.
HGNC HGNC:8591; PAK2.
GenAtlas PAK2.
HPA CAB007794; -.
MIM 605022; gene. [NCBI / EBI]
PharmGKB PA32918; -.
Gene expression databases
ArrayExpress Q13177; -.
Bgee Q13177; -.
CleanEx HS_PAK2; -.
GermOnline ENSG00000180370; Homo sapiens.
Ontologies
GO
GO:0005829; Cellular component: cytosol (inferred from experiment from Reactome).
GO:0016020; Cellular component: membrane (inferred from electronic annotation from UniProtKB-SubCell).
GO:0005634; Cellular component: nucleus (inferred from electronic annotation from UniProtKB-KW).
GO:0048471; Cellular component: perinuclear region of cytoplasm (inferred from electronic annotation from UniProtKB-SubCell).
GO:0005524; Molecular function: ATP binding (inferred from electronic annotation from UniProtKB-KW).
GO:0042802; Molecular function: identical protein binding (inferred from physical interaction from IntAct).
GO:0004674; Molecular function: protein serine/threonine kinase activity (inferred from direct assay from MGI).
GO:0006915; Biological process: apoptosis (inferred from electronic annotation from UniProtKB-KW).
GO:0044419; Biological process: interspecies interaction between organisms (inferred from electronic annotation from UniProtKB-KW).
GO:0006469; Biological process: negative regulation of protein kinase activity (traceable author statement from ProtInc).
GO:0046777; Biological process: protein amino acid autophosphorylation (inferred from direct assay from MGI).
GO:0040008; Biological process: regulation of growth (inferred from electronic annotation from UniProtKB-KW).
GO:0007165; Biological process: signal transduction (traceable author statement from ProtInc).
QuickGo view.
Family and domain databases
InterPro IPR000095; PAK_box_Rho_bd.
IPR000719; Prot_kinase_core.
IPR017441; Protein_kinase_ATP_BS.
IPR017442; Se/Thr_pkinase-rel.
IPR015750; Ser/Thr_Kinase_Pak-rel.
IPR008271; Ser_thr_pkin_AS.
IPR002290; Ser_thr_pkinase.
Graphical view of domain structure.
PANTHER PTHR22986:SF84; Pak_like; 1.
Pfam PF00786; PBD; 1.
PF00069; Pkinase; 1.
Pfam graphical view of domain structure.
ProDom PD000001; Prot_kinase; 1.
[Domain structure / List of seq. sharing at least 1 domain]
SMART SM00285; PBD; 1.
SM00220; S_TKc; 1.
SMART graphical view of domain structure.
PROSITE PS50108; CRIB; 1.
PS00107; PROTEIN_KINASE_ATP; 1.
PS50011; PROTEIN_KINASE_DOM; 1.
PS00108; PROTEIN_KINASE_ST; 1.
PROSITE graphical view of domain structure (profiles).
Proteomic databases
PRIDE Q13177; -.
Genome annotation databases
Ensembl ENSG00000180370; Homo sapiens. [Contig view]
GeneID 5062; -.
KEGG hsa:5062; -.
Phylogenomic databases
HOGENOM Q13177; -.
HOVERGEN Q13177; -.
OMA Q13177; NVDGGAK.
Other
NextBio 19496; -.
PMAP-CutDB Q13177; -.
SOURCE PAK2; Homo sapiens.
ProtoNet Q13177.
UniRef View cluster of proteins with at least 50% / 90% / 100% identity.
Keywords
Allosteric enzyme; Apoptosis; ATP-binding; Cytoplasm; Direct protein sequencing; Growth regulation; Host-virus interaction; Kinase; Lipoprotein; Membrane; Myristate; Nucleotide-binding; Nucleus; Phosphoprotein; Serine/threonine-protein kinase; Transferase; Ubl conjugation.
Features
SEVIEWER logo Feature table viewer FT aligner logo Feature aligner
KeyFrom   To Length Description FTId
CHAIN   1   524  524     Serine/threonine-protein kinase PAK 2. PRO_0000086465
CHAIN   1   212  212     PAK-2p27. PRO_0000304922
CHAIN   213   524  312     PAK-2p34. PRO_0000304923
DOMAIN   74    87  14     CRIB. 
DOMAIN   249   499  251     Protein kinase. 
NP_BIND   255   263  9     ATP (By similarity). 
REGION   69   137  69     Autoregulatory region (By similarity). 
REGION   69   112  44     GTPase-binding (By similarity). 
MOTIF   245   251  7     Nuclear localization signal. 
ACT_SITE   367   367        Proton acceptor (By similarity). 
BINDING   278   278        ATP (By similarity). 
SITE   212   213  2     Cleavage; by caspase-3 or caspase-3-like proteases. 
MOD_RES   2     2        Phosphoserine. 
MOD_RES   58    58        Phosphoserine. 
MOD_RES   60    60        Phosphothreonine. 
MOD_RES   139   139        Phosphotyrosine (By similarity). 
MOD_RES   141   141        Phosphoserine. 
MOD_RES   143   143        Phosphothreonine. 
MOD_RES   169   169        Phosphothreonine. 
MOD_RES   402   402        Phosphothreonine; by autocatalysis (Probable). 
LIPID   213   213        N-myristoyl glycine. 
MUTAGEN   212   212        D->N: Inhibits caspase-mediated cleavage. 
MUTAGEN   213   213        G->A: Abolishes myristoylation of PAK-2p34 and membrane location. 
MUTAGEN   239   243        IVSIG->REGRS: Abolishes nuclear export. 
MUTAGEN   246   248        KKK->MHE: Greatly inhibits nuclear localization. 
MUTAGEN   278   278        K->R: Abolishes kinase activity and autophosphorylation. 
MUTAGEN   402   402        T->A: Abolishes kinase activity and greatly inhibits autophosphorylation of PAK-2p27 and PAK-2p34. 
CONFLICT   90    90        A -> T (in Ref. 3; AAA75468). 
CONFLICT   150   150        F -> L (in Ref. 1; AAA65442). 
CONFLICT   225   225        T -> P (in Ref. 1; AAA65442). 
CONFLICT   258   258        G -> R (in Ref. 2; AAH69613). 
CONFLICT   329   329        G -> R (in Ref. 3; AAA75468). 
CONFLICT   338   338        T -> TA (in Ref. 1; AAA65442). 
Sequence information
Length: 524 AA [This is the length of the unprocessed precursor] Molecular weight: 58043 Da [This is the MW of the unprocessed precursor] CRC64: 00A7CD15F93D4180 [This is a checksum on the sequence] 
        10         20         30         40         50         60 
MSDNGELEDK PPAPPVRMSS TIFSTGGKDP LSANHSLKPL PSVPEEKKPR HKIISIFSGT 

        70         80         90        100        110        120 
EKGSKKKEKE RPEISPPSDF EHTIHVGFDA VTGEFTGMPE QWARLLQTSN ITKLEQKKNP 

       130        140        150        160        170        180 
QAVLDVLKFY DSNTVKQKYL SFTPPEKDGF PSGTPALNAK GTEAPAVVTE EEDDDEETAP 

       190        200        210        220        230        240 
PVIAPRPDHT KSIYTRSVID PVPAPVGDSH VDGAAKSLDK QKKKTKMTDE EIMEKLRTIV 

       250        260        270        280        290        300 
SIGDPKKKYT RYEKIGQGAS GTVFTATDVA LGQEVAIKQI NLQKQPKKEL IINEILVMKE 

       310        320        330        340        350        360 
LKNPNIVNFL DSYLVGDELF VVMEYLAGGS LTDVVTETCM DEAQIAAVCR ECLQALEFLH 

       370        380        390        400        410        420 
ANQVIHRDIK SDNVLLGMEG SVKLTDFGFC AQITPEQSKR STMVGTPYWM APEVVTRKAY 

       430        440        450        460        470        480 
GPKVDIWSLG IMAIEMVEGE PPYLNENPLR ALYLIATNGT PELQNPEKLS PIFRDFLNRC 

       490        500        510        520 
LEMDVEKRGS AKELLQHPFL KLAKPLSSLT PLIMAAKEAM KSNR
Q13177 in FASTA format

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