Reviewed, UniProtKB/Swiss-Prot Q13177 (PAK2_HUMAN)

Names and origin

Protein names

Recommended name:
    Serine/threonine-protein kinase PAK 2
    EC=2.7.11.1
Alternative name(s):
    p21-activated kinase 2
      Short name=PAK-2
    Gamma-PAK
    PAK65
    S6/H4 kinase
    p58
Cleaved into the following 2 chains:
    1- Recommended name:
            PAK-2p27
                Short name=p27
    2- Recommended name:
            PAK-2p34
                Short name=p34
        Alternative name(s):
            C-t-PAK2

Gene names

Name:

PAK2

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	524 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (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. Ref.6 Ref.9 Ref.14
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 structure	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. Interacts with SCRIB. Ref.8 Ref.10 Ref.12 Ref.15
Subcellular location	Serine/threonine-protein kinase PAK 2: Cytoplasm Ref.9 Ref.14 Ref.10. 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. Ref.9 Ref.14 Ref.10
Tissue specificity	Ubiquitously expressed. Higher levels seen in skeletal muscle, ovary, thymus and spleen.
Post-translational modification	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. Ref.5 Ref.7 Ref.11 Ref.13 Ref.16 Ref.17 Ref.19 Ref.20 During apoptosis proteolytically cleaved by caspase-3 or caspase-3-like proteases to yield active PAK-2p34. Ref.6 Ref.7 Ubiquitinated, leading to its proteosomal degradation. Ref.9 PAK-2p34 is myristoylated.
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. Contains 1 CRIB domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Apoptosis Growth regulation Host-virus interaction
Cellular component	Cytoplasm Membrane Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Lipoprotein Myristate Phosphoprotein Ubl conjugation
Technical term	Allosteric enzyme Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	apoptosis Inferred from electronic annotation. Source: UniProtKB-KW interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of protein kinase activity Traceable author statement. Source: ProtInc protein amino acid autophosphorylation Inferred from direct assay. Source: MGI regulation of growth Inferred from electronic annotation. Source: UniProtKB-KW signal transduction Ref.3 Traceable author statement. Source: ProtInc
Cellular component	anchored to membrane Inferred from electronic annotation. Source: UniProtKB-SubCell cytosol Inferred from Experiment. Source: Reactome nucleus Inferred from electronic annotation. Source: UniProtKB-KW perinuclear region of cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW identical protein binding Inferred from physical interaction. Source: IntAct protein serine/threonine kinase activity Inferred from direct assay. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		2	EBI-1045887,EBI-1045887
GIT1	Q9Y2X7	1	EBI-1045887,EBI-466061
GIT2	Q14161	1	EBI-1045887,EBI-1046878
LIMK1	P53667	2	EBI-1045887,EBI-444403
MCM3	P25205	1	EBI-1045887,EBI-355153
MYH10	P35580	1	EBI-1045887,EBI-351758
RAF1	P04049	2	EBI-1045887,EBI-365996

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	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
Regions
	Domain	74 – 87	14	CRIB
	Domain	249 – 499	251	Protein kinase
	Nucleotide binding	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
Sites
	Active site	367	1	Proton acceptor By similarity
	Binding site	278	1	ATP By similarity
	Site	212 – 213	2	Cleavage; by caspase-3 or caspase-3-like proteases
Amino acid modifications
	Modified residue	2	1	Phosphoserine Ref.11
	Modified residue	38	1	N6-acetyllysine Ref.21
	Modified residue	55	1	Phosphoserine Ref.20
	Modified residue	58	1	Phosphoserine Ref.17 Ref.19
	Modified residue	60	1	Phosphothreonine Ref.16
	Modified residue	128	1	N6-acetyllysine Ref.21
	Modified residue	139	1	Phosphotyrosine By similarity
	Modified residue	141	1	Phosphoserine Ref.11 Ref.13 Ref.17 Ref.19 Ref.20
	Modified residue	143	1	Phosphothreonine Ref.11 Ref.20
	Modified residue	169	1	Phosphothreonine Ref.17
	Modified residue	197	1	Phosphoserine Ref.20
	Modified residue	402	1	Phosphothreonine; by autocatalysis Probable
	Lipidation	213	1	N-myristoyl glycine Ref.14
Experimental info
	Mutagenesis	212	1	D → N: Inhibits caspase-mediated cleavage. Ref.6
	Mutagenesis	213	1	G → A: Abolishes myristoylation of PAK-2p34 and membrane location.
	Mutagenesis	239 – 243	5	IVSIG → REGRS: Abolishes nuclear export. Ref.9
	Mutagenesis	246 – 248	3	KKK → MHE: Greatly inhibits nuclear localization. Ref.9
	Mutagenesis	278	1	K → R: Abolishes kinase activity and autophosphorylation. Ref.7
	Mutagenesis	402	1	T → A: Abolishes kinase activity and greatly inhibits autophosphorylation of PAK-2p27 and PAK-2p34. Ref.7
	Sequence conflict	90	1	A → T in AAA75468. Ref.3
	Sequence conflict	150	1	F → L in AAA65442. Ref.1
	Sequence conflict	225	1	T → P in AAA65442. Ref.1
	Sequence conflict	258	1	G → R in AAH69613. Ref.2
	Sequence conflict	329	1	G → R in AAA75468. Ref.3
	Sequence conflict	338	1	T → TA in AAA65442. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q13177-1 [UniParc]. Last modified April 3, 2007. Version 3. Checksum: 00A7CD15F93D4180	FASTA	524	58,043
	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

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	Sells M., Knause U.J., Bagrodia S., Ambrose D., Bokoch G.M., Chernoff J. Submitted (APR-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"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. 14:1970-1978(1995) [PubMed: 7744004] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 32-524, PROTEIN SEQUENCE OF 401-417. Tissue: Placenta.
[4]	Erratum Martin G.A., Bollag G., McCormick F., Abo A. EMBO J. 14:4385-4385(1995) [PubMed: 7556080] [Abstract]
[5]	"Activation of an S6/H4 kinase (PAK 65) from human placenta by intramolecular and intermolecular autophosphorylation." Benner G.E., Dennis P.B., Masaracchia R.A. J. Biol. Chem. 270:21121-21128(1995) [PubMed: 7673144] [Abstract] Cited for: AUTOPHOSPHORYLATION.
[6]	"Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2." Rudel T., Bokoch G.M. Science 276:1571-1574(1997) [PubMed: 9171063] [Abstract] Cited for: CASPASE-3 CLEAVAGE AT ASP-512, FUNCTION, MUTAGENESIS OF ASP-212.
[7]	"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. 273:28733-28739(1998) [PubMed: 9786869] [Abstract] Cited for: CASPASE-3 CLEAVAGE AT ASP-512, AUTOPHOSPHORYLATION, MUTAGENESIS OF LYS-278 AND THR-402.
[8]	"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. 74:11081-11087(2000) [PubMed: 11070003] [Abstract] Cited for: INTERACTION WITH HIV-1 NEF.
[9]	"Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation." Jakobi R., McCarthy C.C., Koeppel M.A., Stringer D.K. J. Biol. Chem. 278:38675-38685(2003) [PubMed: 12853446] [Abstract] Cited for: FUNCTION (PAK-2P34), UBIQUITINATION, SUBCELLULAR LOCATION, MUTAGENESIS OF 239-ILE--GLY-243 AND 246-LYS--LYS-248.
[10]	"Identification and characterization of PS-GAP as a novel regulator of caspase-activated PAK-2." Koeppel M.A., McCarthy C.C., Moertl E., Jakobi R. J. Biol. Chem. 279:53653-53664(2004) [PubMed: 15471851] [Abstract] Cited for: INTERACTION WITH ARHGAP10, SUBCELLULAR LOCATION.
[11]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2; SER-141 AND THR-143, MASS SPECTROMETRY. Tissue: Epithelium.
[12]	"Identification of preferred protein interactions by phage-display of the human Src homology-3 proteome." Kaerkkaeinen S., Hiipakka M., Wang J.-H., Kleino I., Vaehae-Jaakkola M., Renkema G.H., Liss M., Wagner R., Saksela K. EMBO Rep. 7:186-191(2006) [PubMed: 16374509] [Abstract] Cited for: INTERACTION WITH SH3MD4.
[13]	"A probability-based approach for high-throughput protein phosphorylation analysis and site localization." Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P. Nat. Biotechnol. 24:1285-1292(2006) [PubMed: 16964243] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-141, MASS SPECTROMETRY. Tissue: Epithelium.
[14]	"Posttranslational myristoylation of caspase-activated p21-activated protein kinase 2 (PAK2) potentiates late apoptotic events." Vilas G.L., Corvi M.M., Plummer G.J., Seime A.M., Lambkin G.R., Berthiaume L.G. Proc. Natl. Acad. Sci. U.S.A. 103:6542-6547(2006) [PubMed: 16617111] [Abstract] Cited for: FUNCTION (PAK-2P34), MYRISTOYLATION AT GLY-213 (PAK-2P34), SUBCELLULAR LOCATION.
[15]	"Scrib regulates PAK activity during the cell migration process." Nola S., Sebbagh M., Marchetto S., Osmani N., Nourry C., Audebert S., Navarro C., Rachel R., Montcouquiol M., Sans N., Etienne-Manneville S., Borg J.-P., Santoni M.-J. Hum. Mol. Genet. 17:3552-3565(2008) [PubMed: 18716323] [Abstract] Cited for: INTERACTION WITH SCRIB.
[16]	"Phosphoproteome of resting human platelets." Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A. J. Proteome Res. 7:526-534(2008) [PubMed: 18088087] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-60, MASS SPECTROMETRY. Tissue: Platelet.
[17]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-58; SER-141 AND THR-169, MASS SPECTROMETRY.
[18]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[19]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-58 AND SER-141, MASS SPECTROMETRY.
[20]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-55; SER-141; THR-143 AND SER-197, MASS SPECTROMETRY. Tissue: T-cell.
[21]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-38 AND LYS-128, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U24153 mRNA. Translation: AAA65442.1. BC069613 mRNA. Translation: AAH69613.1. U25975 mRNA. Translation: AAA75468.1.
IPI	IPI00419979.
PIR	S58682.
RefSeq	NP_002568.2.
UniGene	Hs.518530
3D structure databases
SMR	Q13177. Positions 77-143, 228-519.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q13177. 47 interactions.
STRING	Q13177.
PTM databases
PhosphoSite	Q13177.
2-D gel databases
OGP	Q13177.
Proteomic databases
PRIDE	Q13177.
Genome annotation databases
Ensembl	ENST00000327134; ENSP00000314067; ENSG00000180370; Homo sapiens. [Genome view]
GeneID	5062.
KEGG	hsa:5062.
UCSC	uc003fwy.2. human.
Organism-specific databases
CTD	5062.
GeneCards	GC03P197955.
H-InvDB	HIX0030815.
HGNC	HGNC:8591. PAK2.
HPA	CAB007794.
MIM	605022. gene.
PharmGKB	PA32918.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG08571.
HOGENOM	HBG755340.
HOVERGEN	Q13177.
InParanoid	Q13177.
OMA	NVDGGAK.
OrthoDB	EOG96MF4W.
PhylomeDB	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_18266. Axon guidance. REACT_578. Apoptosis. REACT_6185. HIV Infection. REACT_6900. Signaling in Immune system.
Gene expression databases
ArrayExpress	Q13177.
Bgee	Q13177.
CleanEx	HS_PAK2.
Genevestigator	Q13177.
GermOnline	ENSG00000180370. Homo sapiens.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000095. PAK_box_Rho_bd. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR017442. Se/Thr_prot_kinase-like_dom. IPR015750. Ser/Thr_kinase_Pak-rel. IPR008271. Ser/Thr_prot_kinase_AS. IPR002290. Ser/Thr_prot_kinase_dom. [Graphical view]
PANTHER	PTHR22986:SF84. Pak_like. 1 hit.
Pfam	PF00786. PBD. 1 hit. PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00285. PBD. 1 hit. SM00220. S_TKc. 1 hit. [Graphical view]
PROSITE	PS50108. CRIB. 1 hit. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	19496.
PMAP-CutDB	Q13177.
SOURCE	Search...

Entry information

Entry name

PAK2_HUMAN

Accession

Primary (citable) accession number: Q13177
Secondary accession number(s): Q13154, Q6ISC3

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	April 3, 2007
Last modified:	January 19, 2010
This is version 109 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.