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

Written2011-04Yuan-Hao Hsu
Department of Chemistry, Biochemistry, Pharmacology, School of Medicine, San Diego, La Jolla, California 92093-0601, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesp21 (CDKN1A)-activated kinase 2
p21 protein (Cdc42/Rac)-activated kinase 2
Alias_symbol (synonym)PAK65
PAKgamma
Other alias
HGNC (Hugo) PAK2
LocusID (NCBI) 5062
Atlas_Id 41634
Location 3q29  [Link to chromosome band 3q29]
Location_base_pair Starts at 196739857 and ends at 196832647 bp from pter ( according to hg19-Feb_2009)  [Mapping PAK2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
PAK2 (3q29) / ECE2 (3q27.1)PAK2 (3q29) / LOC646214 (15q11.2)PAK2 (3q29) / PAK2 (3q29)
PAK2 (3q29) / PTPN11 (12q24.13)PAK2 (3q29) / VGLL3 (3p12.1)

DNA/RNA

Description Pak2 gene at 193763319 to 193859670 bp from pter contains 96352 bases and 34 exons. Pak2 gene at the alternative location starts at 196466728 and ends at 196559518 bp from pter. The PAK2 gene in this location contains 20 exons.

Protein

 
  The Linear schematic of Pak2. Functional domains, including proline rich regions (P), acidic region (A), p21-binding domain (PBD), Cdc42 and Rac interaction and binding sequence (CRIB) and autoinhibitory domain (AID) are designated. Autophosphorylation sites (*) and caspase 3 cleavage site (v) are marked. The regulatory domain is blue; the protein kinase domain is green; the overlapping region between PBD and AID is pink.
Description Pak2 has an N-terminal regulatory domain and a C-terminal catalytic domain. In the regulatory domain, Pak2 have several conserved regions, including an autoinhibitory domain (AID), a p21-binding domain (PBD), dimerization domain, proline-rich regions, and an acidic region. The schematic structure of Pak2 is shown in figure above. The catalytic domain of Pak is a conserved bilobal structure in most of the protein kinases.
Expression Pak2 is 58.8 kDa (524 residues) and expressed ubiquitously in mammalian cells.
Function PAK activation is through disruption of autoinhibition, followed by autophosphorylation. In the inactive state, the AID interacts with the catalytic domain to inhibit its kinase activity. GTP-bound Cdc42 can disrupt autoinhibition, which, in turn, leads to autophosphorylation and activation of PAK. Pak2's basal autophosphorylation activity is observed and Pak2 is autophosphorylated at 5 sites, serines 19, 20, 55, 192 and 197. Additional three phosphorylation sites (serines 141 and 165 and threonine 402) are autophosphorylated in the presence of Cdc42(GTP) and ATP. Autophosphorylation of Thr402 in the activation loop is required for the kinase activity of Pak2.
Pak2 can be activated in response to a lot of stresses. Moderate stresses, like hyperosmolarity, ionizing radiation, DNA-damaging agents and serum-deprivation, induce Pak2 activation in cells and lead to cell cycle arrest at G2/M. Activated Pak2 inhibits translation by phosphorylation of various substrates. Pak2 has specific protein substrates, e.g. histone 4, myosin light chain (MLC), prolactin, c-Abl, eukaryote translation initiation factor 3 (eIF3), eIF4B, eIF4G, and Mnk1. Pak2 recognizes the consensus sequence (K/RRXS).
Pak2 is the only member of the PAK family that is directly activated by caspase 3. When Pak2 is cleaved and activated by caspase 3, Pak2 promotes the morphological and biochemical changes of apoptosis. The pro-apoptosis protease, caspase 3 cleaves Pak2 after Asp 212, and thus produces a p27 fragment containing primarily the regulatory domain, and a p34 fragment containing a small piece of the regulatory domain and the entire catalytic domain. Autophosphorylation results in a constitutively active p34 kinase domain. The nuclear import signal (245-251) is required for nuclear localization. Disruption of the region (197-246), containing nuclear export signal results in the nuclear localization of the Pak2 p34 fragment.
Homology Pak1, Pak2 and Pak3 are highly homologous. The primary sequence of human Pak2 is 72 % identical to Pak1 and 71 % identical to Pak3.

Mutations

Note None is reported.

Implicated in

Note
  
Entity Tumors
Prognosis Huang (2004) showed Pak2 is a negative regulator of Myc and suggested Pak2 may be the product of a tumor suppressor gene. Coniglio (2008) reported Pak2 mediates tumor invasion in breast carcinoma cells. Inhibition of RhoA in Pak2-depleted cells decreases MLC phosphorylation and restores cell invasion. Also, the NF2 tumor suppressor Merlin is a substrate of Pak2. Wilkes (2009) showed that Erbin regulates the function of Merlin through Pak2 binding to Merlin.
  
  
Entity Immunodeficiency
Note Human immunodeficiency virus type 1 HIV-1.
Prognosis Human immunodeficiency virus type 1 Nef associates with a active Pak2 independently of binding to Nck or PIX. Nef recruits the GEF Vav1 to plasma membrane to associate with Pak2.
  

Bibliography

Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms.
Coniglio SJ, Zavarella S, Symons MH.
Mol Cell Biol. 2008 Jun;28(12):4162-72. Epub 2008 Apr 14.
PMID 18411304
 
Differential effects of PAK1-activating mutations reveal activity-dependent and -independent effects on cytoskeletal regulation.
Frost JA, Khokhlatchev A, Stippec S, White MA, Cobb MH.
J Biol Chem. 1998 Oct 23;273(43):28191-8.
PMID 9774440
 
Multisite autophosphorylation of p21-activated protein kinase gamma-PAK as a function of activation.
Gatti A, Huang Z, Tuazon PT, Traugh JA.
J Biol Chem. 1999 Mar 19;274(12):8022-8.
PMID 10075701
 
Analysis of conformational changes during activation of protein kinase Pak2 by amide hydrogen/deuterium exchange.
Hsu YH, Johnson DA, Traugh JA.
J Biol Chem. 2008 Dec 26;283(52):36397-405. Epub 2008 Nov 4.
PMID 18984590
 
Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis.
Hsu YH, Traugh JA.
PLoS One. 2010 Mar 1;5(3):e9455.
PMID 20209159
 
Negative control of the Myc protein by the stress-responsive kinase Pak2.
Huang Z, Traugh JA, Bishop JM.
Mol Cell Biol. 2004 Feb;24(4):1582-94.
PMID 14749374
 
Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation.
Jakobi R, McCarthy CC, Koeppel MA, Stringer DK.
J Biol Chem. 2003 Oct 3;278(40):38675-85. Epub 2003 Jul 9.
PMID 12853446
 
Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization.
Kissil JL, Johnson KC, Eckman MS, Jacks T.
J Biol Chem. 2002 Mar 22;277(12):10394-9. Epub 2002 Jan 8.
PMID 11782491
 
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 LT.
Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13642-7.
PMID 9391079
 
Inhibition of cap-dependent translation via phosphorylation of eIF4G by protein kinase Pak2.
Ling J, Morley SJ, Traugh JA.
EMBO J. 2005 Dec 7;24(23):4094-105. Epub 2005 Nov 10.
PMID 16281055
 
A brain serine/threonine protein kinase activated by Cdc42 and Rac1.
Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L.
Nature. 1994 Jan 6;367(6458):40-6.
PMID 8107774
 
Phosphorylation of Mnk1 by caspase-activated Pak2/gamma-PAK inhibits phosphorylation and interaction of eIF4G with Mnk.
Orton KC, Ling J, Waskiewicz AJ, Cooper JA, Merrick WC, Korneeva NL, Rhoads RE, Sonenberg N, Traugh JA.
J Biol Chem. 2004 Sep 10;279(37):38649-57. Epub 2004 Jul 2.
PMID 15234964
 
Cytostatic p21 G protein-activated protein kinase gamma-PAK.
Roig J, Traugh JA.
Vitam Horm. 2001;62:167-98. (REVIEW)
PMID 11345898
 
Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2.
Rudel T, Bokoch GM.
Science. 1997 Jun 6;276(5318):1571-4.
PMID 9171063
 
Genetic evidence for Pak1 autoinhibition and its release by Cdc42.
Tu H, Wigler M.
Mol Cell Biol. 1999 Jan;19(1):602-11.
PMID 9858584
 
Determinants for substrate phosphorylation by p21-activated protein kinase (gamma-PAK).
Tuazon PT, Spanos WC, Gump EL, Monnig CA, Traugh JA.
Biochemistry. 1997 Dec 23;36(51):16059-64.
PMID 9405039
 
Cleavage and activation of p21-activated protein kinase gamma-PAK by CPP32 (caspase 3). Effects of autophosphorylation on activity.
Walter BN, Huang Z, Jakobi R, Tuazon PT, Alnemri ES, Litwack G, Traugh JA.
J Biol Chem. 1998 Oct 30;273(44):28733-9.
PMID 9786869
 
Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta.
Wilkes MC, Repellin CE, Hong M, Bracamonte M, Penheiter SG, Borg JP, Leof EB.
Dev Cell. 2009 Mar;16(3):433-44.
PMID 19289088
 
A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1.
Zhao ZS, Manser E, Chen XQ, Chong C, Leung T, Lim L.
Mol Cell Biol. 1998 Apr;18(4):2153-63.
PMID 9528787
 

Citation

This paper should be referenced as such :
Hsu, YH
PAK2 (p21 protein (Cdc42/Rac)-activated kinase 2)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(11):928-930.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PAK2ID41634ch3q29.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ]
  8p11 myeloproliferative syndrome (FGFR1)
del(13q) in chronic lymphocytic leukemia


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Lung: Translocations in Squamous Cell Carcinoma


External links

Nomenclature
HGNC (Hugo)PAK2   8591
Cards
AtlasPAK2ID41634ch3q29
Entrez_Gene (NCBI)PAK2  5062  p21 (RAC1) activated kinase 2
AliasesPAK65; PAKgamma
GeneCards (Weizmann)PAK2
Ensembl hg19 (Hinxton)ENSG00000180370 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000180370 [Gene_View]  chr3:196739857-196832647 [Contig_View]  PAK2 [Vega]
ICGC DataPortalENSG00000180370
TCGA cBioPortalPAK2
AceView (NCBI)PAK2
Genatlas (Paris)PAK2
WikiGenes5062
SOURCE (Princeton)PAK2
Genetics Home Reference (NIH)PAK2
Genomic and cartography
GoldenPath hg38 (UCSC)PAK2  -     chr3:196739857-196832647 +  3q29   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PAK2  -     3q29   [Description]    (hg19-Feb_2009)
EnsemblPAK2 - 3q29 [CytoView hg19]  PAK2 - 3q29 [CytoView hg38]
Mapping of homologs : NCBIPAK2 [Mapview hg19]  PAK2 [Mapview hg38]
OMIM605022   
Gene and transcription
Genbank (Entrez)AI140979 AK291339 BC031667 BC046197 BC063539
RefSeq transcript (Entrez)NM_002577
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PAK2
Cluster EST : UnigeneHs.518530 [ NCBI ]
CGAP (NCI)Hs.518530
Alternative Splicing GalleryENSG00000180370
Gene ExpressionPAK2 [ NCBI-GEO ]   PAK2 [ EBI - ARRAY_EXPRESS ]   PAK2 [ SEEK ]   PAK2 [ MEM ]
Gene Expression Viewer (FireBrowse)PAK2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5062
GTEX Portal (Tissue expression)PAK2
Human Protein AtlasENSG00000180370-PAK2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13177   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ13177  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ13177
Splice isoforms : SwissVarQ13177
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
PhosPhoSitePlusQ13177
Domaine pattern : Prosite (Expaxy)CRIB (PS50108)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)CRIB_dom    Kinase-like_dom    PAK_BD    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_kinase_AS   
Domain families : Pfam (Sanger)PBD (PF00786)    Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00786    pfam00069   
Domain families : Smart (EMBL)PBD (SM00285)  S_TKc (SM00220)  
Conserved Domain (NCBI)PAK2
DMDM Disease mutations5062
Blocks (Seattle)PAK2
PDB (SRS)3PCS   
PDB (PDBSum)3PCS   
PDB (IMB)3PCS   
PDB (RSDB)3PCS   
Structural Biology KnowledgeBase3PCS   
SCOP (Structural Classification of Proteins)3PCS   
CATH (Classification of proteins structures)3PCS   
SuperfamilyQ13177
Human Protein Atlas [tissue]ENSG00000180370-PAK2 [tissue]
Peptide AtlasQ13177
HPRD05428
IPIIPI00555621   IPI00419979   IPI00926695   
Protein Interaction databases
DIP (DOE-UCLA)Q13177
IntAct (EBI)Q13177
FunCoupENSG00000180370
BioGRIDPAK2
STRING (EMBL)PAK2
ZODIACPAK2
Ontologies - Pathways
QuickGOQ13177
Ontology : AmiGOmitotic cell cycle  stimulatory C-type lectin receptor signaling pathway  protein kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  signal transducer, downstream of receptor, with serine/threonine kinase activity  protein binding  ATP binding  nucleus  cytoplasm  cytosol  cytosol  plasma membrane  protein phosphorylation  negative regulation of protein kinase activity  apoptotic process  signal transduction  viral process  phosphorylation  peptidyl-serine phosphorylation  protein kinase binding  signal transduction by protein phosphorylation  protein tyrosine kinase activator activity  small GTPase binding  T cell costimulation  Fc-epsilon receptor signaling pathway  regulation of growth  identical protein binding  negative regulation of apoptotic process  cadherin binding  protein autophosphorylation  vascular endothelial growth factor receptor signaling pathway  Rac GTPase binding  perinuclear region of cytoplasm  regulation of defense response to virus by virus  positive regulation of peptidyl-tyrosine phosphorylation  T cell receptor signaling pathway  dendritic spine development  positive regulation of protein tyrosine kinase activity  cellular response to organic cyclic compound  positive regulation of extrinsic apoptotic signaling pathway  negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis  
Ontology : EGO-EBImitotic cell cycle  stimulatory C-type lectin receptor signaling pathway  protein kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  signal transducer, downstream of receptor, with serine/threonine kinase activity  protein binding  ATP binding  nucleus  cytoplasm  cytosol  cytosol  plasma membrane  protein phosphorylation  negative regulation of protein kinase activity  apoptotic process  signal transduction  viral process  phosphorylation  peptidyl-serine phosphorylation  protein kinase binding  signal transduction by protein phosphorylation  protein tyrosine kinase activator activity  small GTPase binding  T cell costimulation  Fc-epsilon receptor signaling pathway  regulation of growth  identical protein binding  negative regulation of apoptotic process  cadherin binding  protein autophosphorylation  vascular endothelial growth factor receptor signaling pathway  Rac GTPase binding  perinuclear region of cytoplasm  regulation of defense response to virus by virus  positive regulation of peptidyl-tyrosine phosphorylation  T cell receptor signaling pathway  dendritic spine development  positive regulation of protein tyrosine kinase activity  cellular response to organic cyclic compound  positive regulation of extrinsic apoptotic signaling pathway  negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis  
Pathways : BIOCARTAHIV-I Nef: negative effector of Fas and TNF [Genes]    Fc Epsilon Receptor I Signaling in Mast Cells [Genes]    FAS signaling pathway ( CD95 ) [Genes]    TNFR1 Signaling Pathway [Genes]    Agrin in Postsynaptic Differentiation [Genes]    MAPKinase Signaling Pathway [Genes]   
Pathways : KEGG   
REACTOMEQ13177 [protein]
REACTOME PathwaysR-HSA-5687128 [pathway]   
NDEx NetworkPAK2
Atlas of Cancer Signalling NetworkPAK2
Wikipedia pathwaysPAK2
Orthology - Evolution
OrthoDB5062
GeneTree (enSembl)ENSG00000180370
Phylogenetic Trees/Animal Genes : TreeFamPAK2
HOVERGENQ13177
HOGENOMQ13177
Homologs : HomoloGenePAK2
Homology/Alignments : Family Browser (UCSC)PAK2
Gene fusions - Rearrangements
Fusion : MitelmanPAK2/ECE2 [3q29/3q27.1]  
Fusion : MitelmanPAK2/VGLL3 [3q29/3p12.1]  [t(3;3)(p12;q29)]  
Fusion: TCGAPAK2 3q29 ECE2 3q27.1 LUSC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPAK2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PAK2
dbVarPAK2
ClinVarPAK2
1000_GenomesPAK2 
Exome Variant ServerPAK2
ExAC (Exome Aggregation Consortium)ENSG00000180370
GNOMAD BrowserENSG00000180370
Genetic variants : HAPMAP5062
Genomic Variants (DGV)PAK2 [DGVbeta]
DECIPHERPAK2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPAK2 
Mutations
ICGC Data PortalPAK2 
TCGA Data PortalPAK2 
Broad Tumor PortalPAK2
OASIS PortalPAK2 [ Somatic mutations - Copy number]
Mutations and Diseases : HGMDPAK2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PAK2
DgiDB (Drug Gene Interaction Database)PAK2
DoCM (Curated mutations)PAK2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PAK2 (select a term)
intoGenPAK2
NCG5 (London)PAK2
Cancer3DPAK2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605022   
Orphanet
MedgenPAK2
Genetic Testing Registry PAK2
NextProtQ13177 [Medical]
TSGene5062
GENETestsPAK2
Target ValidationPAK2
Huge Navigator PAK2 [HugePedia]
snp3D : Map Gene to Disease5062
BioCentury BCIQPAK2
ClinGenPAK2 (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5062
Chemical/Pharm GKB GenePA32918
Clinical trialPAK2
Miscellaneous
canSAR (ICR)PAK2 (select the gene name)
Probes
Litterature
PubMed177 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePAK2
EVEXPAK2
GoPubMedPAK2
iHOPPAK2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 12 16:29:41 CEST 2017

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