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Protein

Serine/threonine-protein kinase PAK 4

Gene

PAK4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, growth, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN.8 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Inhibited by FAM212A/INKA1; which inhibits the serine/threonine-protein kinase activity by binding PAK4 in a substrate-like manner (PubMed:26607847).1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei350ATPPROSITE-ProRule annotationCombined sources1 Publication1
Active sitei440Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi327 – 335ATPPROSITE-ProRule annotationCombined sources1 Publication9
Nucleotide bindingi396 – 398ATPCombined sources1 Publication3
Nucleotide bindingi458 – 460ATPCombined sources1 Publication3

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • cadherin binding involved in cell-cell adhesion Source: BHF-UCL
  • protein kinase activity Source: ProtInc
  • protein serine/threonine kinase activity Source: UniProtKB
  • Rac GTPase binding Source: GO_Central

GO - Biological processi

  • actin cytoskeleton organization Source: GO_Central
  • activation of protein kinase activity Source: GO_Central
  • apoptotic process Source: UniProtKB
  • cell cycle Source: UniProtKB-KW
  • cell growth Source: UniProtKB
  • cell migration Source: UniProtKB
  • cell proliferation Source: UniProtKB
  • cellular response to organic cyclic compound Source: Ensembl
  • cytoskeleton organization Source: UniProtKB
  • dendritic spine development Source: Ensembl
  • negative regulation of endothelial cell apoptotic process Source: BHF-UCL
  • positive regulation of angiogenesis Source: BHF-UCL
  • regulation of apoptotic process Source: GO_Central
  • regulation of MAPK cascade Source: GO_Central
  • regulation of mitotic cell cycle Source: GO_Central
  • Rho protein signal transduction Source: GO_Central
  • signal transduction Source: UniProtKB
  • signal transduction by protein phosphorylation Source: GO_Central
  • stress-activated protein kinase signaling cascade Source: GO_Central

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processApoptosis, Cell cycle
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.1 2681
ReactomeiR-HSA-428540 Activation of RAC1
SignaLinkiO96013
SIGNORiO96013

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase PAK 4 (EC:2.7.11.1)
Alternative name(s):
p21-activated kinase 4
Short name:
PAK-4
Gene namesi
Name:PAK4
Synonyms:KIAA1142
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

EuPathDBiHostDB:ENSG00000130669.17
HGNCiHGNC:16059 PAK4
MIMi605451 gene
neXtProtiNX_O96013

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi445S → N: Approximately 30-fold increased autophosphorylation (constitutively active mutant). 1 Publication1
Mutagenesisi474S → E: Approximately 3-fold increased autophosphorylation. 1 Publication1

Organism-specific databases

DisGeNETi10298
OpenTargetsiENSG00000130669
PharmGKBiPA32920

Chemistry databases

ChEMBLiCHEMBL4482
GuidetoPHARMACOLOGYi2136

Polymorphism and mutation databases

BioMutaiPAK4

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000864741 – 591Serine/threonine-protein kinase PAK 4Add BLAST591

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei41PhosphoserineCombined sources1
Modified residuei78N6-methyllysineCombined sources1
Modified residuei104PhosphoserineCombined sources1
Modified residuei148PhosphoserineCombined sources1
Modified residuei167PhosphoserineCombined sources1
Modified residuei181PhosphoserineCombined sources1
Modified residuei187PhosphothreonineCombined sources1
Modified residuei195PhosphoserineCombined sources1
Modified residuei207PhosphothreonineCombined sources1
Modified residuei258PhosphoserineCombined sources1
Modified residuei267PhosphoserineCombined sources1
Modified residuei291PhosphoserineCombined sources1
Modified residuei474Phosphoserine; by autocatalysisCombined sources1 Publication1

Post-translational modificationi

Autophosphorylated on serine residues when activated by CDC42/p21.1 Publication
Phosphorylated on tyrosine residues upon stimulation of FGFR2.By similarity

Keywords - PTMi

Methylation, Phosphoprotein

Proteomic databases

EPDiO96013
MaxQBiO96013
PaxDbiO96013
PeptideAtlasiO96013
PRIDEiO96013

PTM databases

iPTMnetiO96013
PhosphoSitePlusiO96013

Expressioni

Tissue specificityi

Highest expression in prostate, testis and colon.

Gene expression databases

BgeeiENSG00000130669
CleanExiHS_PAK4
ExpressionAtlasiO96013 baseline and differential
GenevisibleiO96013 HS

Organism-specific databases

HPAiCAB025747
CAB044670
HPA070175
HPA072220

Interactioni

Subunit structurei

Interacts with FGFR2 and GRB2 (By similarity). Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and weakly with RAC1 (PubMed:15827085). Interacts with FAM212A/INKA1 (PubMed:26607847).By similarity2 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • cadherin binding involved in cell-cell adhesion Source: BHF-UCL
  • Rac GTPase binding Source: GO_Central

Protein-protein interaction databases

BioGridi115586, 63 interactors
DIPiDIP-39742N
IntActiO96013, 29 interactors
MINTiO96013
STRINGi9606.ENSP00000351049

Chemistry databases

BindingDBiO96013

Structurei

Secondary structure

1591
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi15 – 26Combined sources12
Turni27 – 30Combined sources4
Beta strandi31 – 34Combined sources4
Helixi37 – 39Combined sources3
Turni40 – 42Combined sources3
Turni46 – 48Combined sources3
Helixi301 – 311Combined sources11
Beta strandi312 – 315Combined sources4
Helixi317 – 319Combined sources3
Beta strandi321 – 329Combined sources9
Beta strandi331 – 333Combined sources3
Beta strandi334 – 340Combined sources7
Turni341 – 343Combined sources3
Beta strandi346 – 353Combined sources8
Helixi354 – 356Combined sources3
Helixi360 – 362Combined sources3
Helixi363 – 369Combined sources7
Turni370 – 372Combined sources3
Beta strandi381 – 387Combined sources7
Beta strandi390 – 395Combined sources6
Helixi403 – 409Combined sources7
Helixi414 – 433Combined sources20
Helixi443 – 445Combined sources3
Beta strandi446 – 448Combined sources3
Beta strandi454 – 456Combined sources3
Helixi459 – 461Combined sources3
Beta strandi467 – 469Combined sources3
Beta strandi475 – 477Combined sources3
Helixi479 – 481Combined sources3
Helixi484 – 487Combined sources4
Helixi495 – 510Combined sources16
Turni514 – 517Combined sources4
Helixi520 – 529Combined sources10
Helixi538 – 540Combined sources3
Helixi543 – 552Combined sources10
Turni557 – 559Combined sources3
Helixi563 – 566Combined sources4
Helixi570 – 574Combined sources5
Helixi578 – 581Combined sources4
Helixi582 – 584Combined sources3
Turni586 – 588Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2BVAX-ray2.30A/B300-591[»]
2CDZX-ray2.30A291-591[»]
2J0IX-ray1.60A291-591[»]
2OV2X-ray2.10I/J/K/L/M/N/O/P10-44[»]
2Q0NX-ray1.75A291-591[»]
2X4ZX-ray2.10A297-591[»]
4APPX-ray2.20A300-591[»]
4FIEX-ray3.11A/B5-591[»]
4FIFX-ray2.60A/B286-591[»]
C/D49-56[»]
4FIGX-ray3.01A/B286-591[»]
4FIHX-ray1.97A286-591[»]
4FIIX-ray2.00A286-591[»]
B49-56[»]
4FIJX-ray2.30A286-591[»]
4JDHX-ray2.00A286-591[»]
4JDIX-ray1.85A286-591[»]
4JDJX-ray2.30A286-591[»]
4JDKX-ray2.40A286-591[»]
4L67X-ray2.80A300-591[»]
B36-60[»]
4NJDX-ray2.50A300-591[»]
4O0VX-ray2.80A300-591[»]
4O0XX-ray2.48A300-591[»]
4O0YX-ray2.20A300-591[»]
4XBRX-ray2.94A278-591[»]
4XBUX-ray2.06A286-591[»]
5BMSX-ray2.90A300-591[»]
5I0BX-ray3.09A300-591[»]
5UPKX-ray2.40A1-45[»]
B286-591[»]
5UPLX-ray3.00A2-591[»]
5VEDX-ray2.30A286-591[»]
5VEEX-ray2.50A286-591[»]
5VEFX-ray1.75A286-591[»]
5XVAX-ray1.85A300-591[»]
5XVFX-ray2.65A300-588[»]
5XVGX-ray2.10A300-591[»]
ProteinModelPortaliO96013
SMRiO96013
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO96013

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini11 – 24CRIBPROSITE-ProRule annotationAdd BLAST14
Domaini321 – 572Protein kinasePROSITE-ProRule annotationAdd BLAST252

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni25 – 320LinkerAdd BLAST296
Regioni298 – 323GEF-interaction domain (GID)Add BLAST26

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi105 – 108Poly-Pro4
Compositional biasi242 – 247Poly-Ser6

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0578 Eukaryota
ENOG410XP4K LUCA
GeneTreeiENSGT00910000143994
HOVERGENiHBG108518
InParanoidiO96013
KOiK05734
OMAiRQENGMP
OrthoDBiEOG091G0OT5
PhylomeDBiO96013
TreeFamiTF105352

Family and domain databases

CDDicd01093 CRIB_PAK_like, 1 hit
Gene3Di3.90.810.10, 1 hit
InterProiView protein in InterPro
IPR000095 CRIB_dom
IPR036936 CRIB_dom_sf
IPR011009 Kinase-like_dom_sf
IPR033923 PAK_BD
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
PfamiView protein in Pfam
PF00786 PBD, 1 hit
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00285 PBD, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50108 CRIB, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O96013-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MFGKRKKRVE ISAPSNFEHR VHTGFDQHEQ KFTGLPRQWQ SLIEESARRP
60 70 80 90 100
KPLVDPACIT SIQPGAPKTI VRGSKGAKDG ALTLLLDEFE NMSVTRSNSL
110 120 130 140 150
RRDSPPPPAR ARQENGMPEE PATTARGGPG KAGSRGRFAG HSEAGGGSGD
160 170 180 190 200
RRRAGPEKRP KSSREGSGGP QESSRDKRPL SGPDVGTPQP AGLASGAKLA
210 220 230 240 250
AGRPFNTYPR ADTDHPSRGA QGEPHDVAPN GPSAGGLAIP QSSSSSSRPP
260 270 280 290 300
TRARGAPSPG VLGPHASEPQ LAPPACTPAA PAVPGPPGPR SPQREPQRVS
310 320 330 340 350
HEQFRAALQL VVDPGDPRSY LDNFIKIGEG STGIVCIATV RSSGKLVAVK
360 370 380 390 400
KMDLRKQQRR ELLFNEVVIM RDYQHENVVE MYNSYLVGDE LWVVMEFLEG
410 420 430 440 450
GALTDIVTHT RMNEEQIAAV CLAVLQALSV LHAQGVIHRD IKSDSILLTH
460 470 480 490 500
DGRVKLSDFG FCAQVSKEVP RRKSLVGTPY WMAPELISRL PYGPEVDIWS
510 520 530 540 550
LGIMVIEMVD GEPPYFNEPP LKAMKMIRDN LPPRLKNLHK VSPSLKGFLD
560 570 580 590
RLLVRDPAQR ATAAELLKHP FLAKAGPPAS IVPLMRQNRT R
Length:591
Mass (Da):64,072
Last modified:May 1, 1999 - v1
Checksum:i04C2A5C0B06427D5
GO
Isoform 2 (identifier: O96013-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     120-120: E → K
     121-285: Missing.

Note: No experimental confirmation available.
Show »
Length:426
Mass (Da):47,924
Checksum:i505879690593E93A
GO
Isoform 3 (identifier: O96013-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     69-221: Missing.

Show »
Length:438
Mass (Da):48,268
Checksum:i4A596EBBCECE9883
GO
Isoform 4 (identifier: O96013-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     132-221: Missing.

Note: No experimental confirmation available.
Show »
Length:501
Mass (Da):54,940
Checksum:i6EE6240ECE65E79D
GO

Sequence cautioni

The sequence BAA86456 differs from that shown. Reason: Erroneous initiation.Curated
The sequence BAC11166 differs from that shown. Reason: Erroneous initiation.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_040970135R → Q1 PublicationCorresponds to variant dbSNP:rs56099436Ensembl.1
Natural variantiVAR_040971139A → T1 PublicationCorresponds to variant dbSNP:rs35655056Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_01757269 – 221Missing in isoform 3. 3 PublicationsAdd BLAST153
Alternative sequenceiVSP_004892120E → K in isoform 2. 1 Publication1
Alternative sequenceiVSP_004893121 – 285Missing in isoform 2. 1 PublicationAdd BLAST165
Alternative sequenceiVSP_017573132 – 221Missing in isoform 4. 1 PublicationAdd BLAST90

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ011855 mRNA Translation: CAA09820.1
AF005046 mRNA Translation: AAD01210.1
AB032968 mRNA Translation: BAA86456.1 Different initiation.
AK074728 mRNA Translation: BAC11166.1 Different initiation.
AK294586 mRNA Translation: BAG57777.1
AL834236 mRNA Translation: CAD38914.2
CH471126 Genomic DNA Translation: EAW56861.1
BC002921 mRNA Translation: AAH02921.1
BC011368 mRNA Translation: AAH11368.1
BC025282 mRNA Translation: AAH25282.1
BC034511 mRNA Translation: AAH34511.1
CCDSiCCDS12528.1 [O96013-1]
CCDS33019.1 [O96013-3]
RefSeqiNP_001014831.1, NM_001014831.2 [O96013-1]
NP_001014832.1, NM_001014832.1 [O96013-1]
NP_001014834.1, NM_001014834.2 [O96013-3]
NP_001014835.1, NM_001014835.1 [O96013-3]
NP_005875.1, NM_005884.3 [O96013-1]
XP_011524618.1, XM_011526316.1 [O96013-1]
XP_011524619.1, XM_011526317.2 [O96013-1]
XP_011524620.1, XM_011526318.2 [O96013-1]
XP_011524621.1, XM_011526319.2 [O96013-1]
XP_011524622.1, XM_011526320.1 [O96013-3]
UniGeneiHs.20447

Genome annotation databases

EnsembliENST00000321944; ENSP00000326864; ENSG00000130669 [O96013-4]
ENST00000358301; ENSP00000351049; ENSG00000130669 [O96013-1]
ENST00000360442; ENSP00000353625; ENSG00000130669 [O96013-1]
ENST00000593690; ENSP00000469413; ENSG00000130669 [O96013-1]
ENST00000599386; ENSP00000471157; ENSG00000130669 [O96013-3]
ENST00000599470; ENSP00000470284; ENSG00000130669 [O96013-3]
GeneIDi10298
KEGGihsa:10298
UCSCiuc002okj.2 human [O96013-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiPAK4_HUMAN
AccessioniPrimary (citable) accession number: O96013
Secondary accession number(s): B4DGG6
, Q8N4E1, Q8NCH5, Q8NDE3, Q9BU33, Q9ULS8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 24, 2001
Last sequence update: May 1, 1999
Last modified: April 25, 2018
This is version 193 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
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Main funding by: National Institutes of Health