Reviewed, UniProtKB/Swiss-Prot P35465 (PAK1_RAT)

Names and origin

Protein names

Recommended name:
    Serine/threonine-protein kinase PAK 1
    EC=2.7.11.1
Alternative name(s):
    p21-activated kinase 1
      Short name=PAK-1
    p68-PAK
    Alpha-PAK
    Protein kinase MUK2

Gene names

Name:

Pak1

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	544 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	The activated kinase acts on a variety of targets. Likely to be the GTPase effector that links the Rho-related GTPases to the JNK MAP kinase pathway. Activated by CDC42 and RAC1. Involved in dissolution of stress fibers and reorganization of focal complexes. Involved in regulation of microtubule biogenesis through phosphorylation of TBCB. Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2 By similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
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-422 and allows the kinase domain to adopt an active structure. Also activated by binding to GTP-bound CDC42, independent of the phosphorylation state of Thr-422. Phosphorylation of Thr-84 by OXSR1 inhibits this activation By similarity.
Subunit structure	Homodimer in its autoinhibited state. Active as monomer. Interacts tightly with GTP-bound but not GDP-bound CDC42/P21 and RAC1. Binds to the caspase-cleaved p110 isoform of CDC2L1 and CDC2L2, p110C, but not the full-length proteins. Component of cytoplasmic complexes, which also contain PXN, ARHGEF6 and GIT1. Interacts with ARHGEF7. Also interacts with CRIPAK. Interacts with SCRIB By similarity.
Tissue specificity	Expressed predominantly in the brain, with higher expression in neuronal groups associated with motor function, and at lower levels in the spleen. Ref.4
Developmental stage	Found in the embryonic CNS with little expression elsewhere.
Post-translational modification	Autophosphorylated when activated by CDC42/p21 and RAC1 By similarity.
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
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Allosteric enzyme
Gene Ontology (GO)
Biological process	cellular response to insulin stimulus Inferred from direct assay. Source: RGD cellular response to stress Inferred from direct assay. Source: RGD neuron projection morphogenesis Inferred from mutant phenotype. Source: RGD positive regulation of JUN kinase activity Inferred from sequence or structural similarity. Source: UniProtKB protein amino acid autophosphorylation Inferred from sequence or structural similarity. Source: UniProtKB protein kinase cascade Traceable author statement. Source: RGD regulation of actin cytoskeleton organization Inferred from mutant phenotype. Source: RGD response to hypoxia Inferred from direct assay. Source: RGD small GTPase mediated signal transduction Ref.1 Traceable author statement. Source: RGD
Cellular component	Z disc Inferred from direct assay. Source: RGD axon Inferred from direct assay. Source: RGD cytosol Inferred from direct assay. Source: RGD dendrite Inferred from direct assay. Source: RGD intercalated disc Inferred from direct assay. Source: RGD membrane fraction Inferred from direct assay. Source: RGD nuclear membrane Inferred from direct assay. Source: RGD
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW MAP kinase kinase kinase activity Traceable author statement. Source: RGD protein kinase binding Inferred from physical interaction. Source: RGD
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CDC42	P60953	1	EBI-444379,EBI-81752	From a different organism.
CDC42	P60953-2	1	EBI-444379,EBI-287394	From a different organism.
OXSR1	O95747	1	EBI-444379,EBI-620853	From a different organism.
Vim	P20152	2	EBI-444379,EBI-299269	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 544

544

Serine/threonine-protein kinase PAK 1

PRO_0000086462

Regions

Domain

75 – 88

14

CRIB

Domain

269 – 520

252

Protein kinase

Nucleotide binding

275 – 283

9

ATP By similarity

Region

70 – 140

71

Autoregulatory region By similarity

Region

70 – 105

36

GTPase-binding

Region

132 – 269

138

Interaction with CRIPAK By similarity

Sites

Active site

388

1

Proton acceptor By similarity

Binding site

298

1

ATP By similarity

Amino acid modifications

Modified residue

21

1

Phosphoserine; by autocatalysis Probable

Modified residue

57

1

Phosphoserine; by autocatalysis Probable

Modified residue

84

1

Phosphothreonine; by OXSR1 Ref.8

Modified residue

144

1

Phosphoserine; by autocatalysis Probable

Modified residue

149

1

Phosphoserine; by autocatalysis Probable

Modified residue

198

1

Phosphoserine; by autocatalysis Probable

Modified residue

203

1

Phosphoserine; by autocatalysis Ref.5

Modified residue

211

1

Phosphothreonine By similarity

Modified residue

219

1

Phosphoserine By similarity

Modified residue

222

1

Phosphoserine By similarity

Modified residue

224

1

Phosphothreonine By similarity

Modified residue

229

1

Phosphothreonine By similarity

Modified residue

255

1

N6-acetyllysine By similarity

Modified residue

422

1

Phosphothreonine; by autocatalysis Ref.5

Modified residue

473

1

Phosphotyrosine By similarity

Experimental info

Mutagenesis

84

1

T → A: Constitutively active. Ref.8

Mutagenesis

84

1

T → E: Inhibits activation by binding to CDC42. Ref.8

Mutagenesis

144

1

S → A: Decreases activity; when associated with A-149. Ref.7

Mutagenesis

149

1

S → A: Decreases activity; when associated with A-144. Ref.7

Mutagenesis

422

1

T → A: Decreases activity. Ref.7

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

544

Helix Strand Turn

Details...

Beta strand

88 – 90

3

Helix

91 – 93

3

Beta strand

95 – 98

4

Helix

101 – 106

6

Beta strand

107 – 109

3

Beta strand

113 – 115

3

Sequences

	Sequence		Length	Mass (Da)
	P35465-1 [UniParc]. Last modified December 15, 1998. Version 3. Checksum: 93BE32D8222F5B7B	FASTA	544	60,578
	10 20 30 40 50 60 MSNNGLDVQD KPPAPPMRNT STMIGAGSKD PGTLNHGSKP LPPNPEEKKK KDRFYRSILA 70 80 90 100 110 120 GDKTNKKKEK ERPEISLPSD FEHTIHVGFD AVTGEFTGMP EQWARLLQTS NITKSEQKKN 130 140 150 160 170 180 PQAVLDVLEF YNSKKTSNSQ KYMSFTDKSA EDYNSSNTLN VKTVSETPAV PPVSEDEDDD 190 200 210 220 230 240 DDATPPPVIA PRPEHTKSVY TRSVIEPLPV TPTRDVATSP ISPTENNTTP PDALTRNTEK 250 260 270 280 290 300 QKKKPKMSDE EILEKLRSIV SVGDPKKKYT RFEKIGQGAS GTVYTAMDVA TGQEVAIKQM 310 320 330 340 350 360 NLQQQPKKEL IINEILVMRE NKNPNIVNYL DSYLVGDELW VVMEYLAGGS LTDVVTETCM 370 380 390 400 410 420 DEGQIAAVCR ECLQALEFLH SNQVIHRDIK SDNILLGMDG SVKLTDFGFC AQITPEQSKR 430 440 450 460 470 480 STMVGTPYWM APEVVTRKAY GPKVDIWSLG IMAIEMIEGE PPYLNENPLR ALYLIATNGT 490 500 510 520 530 540 PELQNPEKLS AIFRDFLNRC LEMDVEKRGS AKELLQHQFL KIAKPLSSLT PLIAAAKEAT KNNH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A brain serine/threonine protein kinase activated by Cdc42 and Rac1." Manser E., Leung T., Salihuddin H., Zhao Z.-S., Lim L. Nature 367:40-46(1994) [PubMed: 8107774] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	Zhao Z.-S. Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION.
[3]	Osada S., Izawa M., Saito R., Mizuno K., Suzuki A., Hirai S., Ohno S. Submitted (JUL-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family." Manser E., Chong C., Zhao Z.-S., Leung T., Michael G., Hall C., Lim L. J. Biol. Chem. 270:25070-25078(1995) [PubMed: 7559638] [Abstract] Cited for: TISSUE SPECIFICITY.
[5]	"Expression of constitutively active alpha-PAK reveals effects of the kinase on actin and focal complexes." Manser E., Huang H.Y., Loo T.H., Chen X.Q., Dong J.M., Leung T., Lim L. Mol. Cell. Biol. 17:1129-1143(1997) [PubMed: 9032240] [Abstract] Cited for: PHOSPHORYLATION AT SER-21; SER-57; SER-144; SER-149; SER-198; SER-203 AND THR-422.
[6]	"Delineation of the Cdc42/Rac-binding domain of p21-activated kinase." Thompson G., Owen D., Chalk P.A., Lowe P.N. Biochemistry 37:7885-7891(1998) [PubMed: 9601050] [Abstract] Cited for: DOMAIN GTPASE BINDING.
[7]	"The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity." Chong C., Tan L., Lim L., Manser E. J. Biol. Chem. 276:17347-17353(2001) [PubMed: 11278486] [Abstract] Cited for: MUTAGENESIS OF SER-144; SER-149 AND THR-422.
[8]	"Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily." Chen W., Yazicioglu M., Cobb M.H. J. Biol. Chem. 279:11129-11136(2004) [PubMed: 14707132] [Abstract] Cited for: FUNCTION, ENZYME REGULATION, INTERACTION WITH OXSR1, PHOSPHORYLATION AT THR-84, MUTAGENESIS OF THR-84.
[9]	"Phosphoproteomic analysis of rat liver by high capacity IMAC and LC-MS/MS." Moser K., White F.M. J. Proteome Res. 5:98-104(2006) [PubMed: 16396499] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-144, MASS SPECTROMETRY. Tissue: Liver.
[10]	"Structure of Cdc42 bound to the GTPase binding domain of PAK." Morreale A., Venkatesan M., Mott H.R., Owen D., Nietlispach D., Lowe P.N., Laue E.D. Nat. Struct. Biol. 7:384-388(2000) [PubMed: 10802735] [Abstract] Cited for: STRUCTURE BY NMR OF 75-118 IN COMPLEX WITH CDC42.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

U23443 mRNA. Translation: AAB95646.1.
U49953 mRNA. Translation: AAB61533.1.

IPI

IPI00198685.

PIR

S40482.

RefSeq

NP_058894.1.

UniGene

Rn.9149

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1E0A	NMR	-	B	75-118	[»]

SMR

P35465. Positions 78-147, 248-540.

ModBase

Search...

Protein-protein interaction databases

IntAct

P35465. 4 interactions.

STRING

P35465.

PTM databases

PhosphoSite

P35465.

Proteomic databases

PRIDE

P35465.

Genome annotation databases

Ensembl

ENSRNOT00000046151; ENSRNOP00000047543; ENSRNOG00000029784; Rattus norvegicus. [Genome view]
ENSRNOT00000049321; ENSRNOP00000045832; ENSRNOG00000029784; Rattus norvegicus. [Genome view]

GeneID

29431.

KEGG

rno:29431.

UCSC

NM_017198. rat.

Organism-specific databases

CTD

29431.

RGD

3250. Pak1.

Phylogenomic databases

HOVERGEN

P35465.

OMA

EATKNNH.

Enzyme and pathway databases

BRENDA

2.7.11.1. 248.

Gene expression databases

ArrayExpress

P35465.

Genevestigator

P35465.

GermOnline

ENSRNOG00000029784. Rattus norvegicus.

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]

PANTHER

PTHR22986:SF84. Pak_like. 1 hit.

Pfam

PF00786. PBD. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]

ProDom

PD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

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

609154.

Entry information

Entry name

PAK1_RAT

Accession

Primary (citable) accession number: P35465
Secondary accession number(s): Q62934

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	December 15, 1998
Last modified:	November 3, 2009
This is version 106 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)