P30291 (WEE1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Wee1-like protein kinase
Short name=WEE1hu
EC=2.7.10.2

Alternative name(s):
Wee1A kinase

Gene names

Name:

WEE1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	646 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Cofactor	Binds 2 magnesium ions per subunit.
Enzyme regulation	Synthesis is increased during S and G2 phases, presumably by an increase in transcription; activity is decreased by phosphorylation during m phase. Protein levels fall in M phase as a result of decreased synthesis combined with degradation. Activity seems to be negatively regulated by phosphorylation upon entry into mitosis, although N-terminal phosphorylation might also regulate the protein stability via protection from proteolysis or might regulate the subcellular location.
Subcellular location	Nucleus.
Post-translational modification	Phosphorylated during M and G1 phases. Also autophosphorylated. Phosphorylation at Ser-642 by BRSK1 and BRSK2 in post-mitotic neurons, leads to down-regulate WEE1 activity in polarized neurons. Phosphorylated at Ser-53 and Ser-123 by PLK1 and CDK1, respectively, generating an signal for degradation that can be recognized by the SCF(BTRC) complex, leading to its ubiquitination and degradation at the onset of G2/M phase. Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ubiquitinated and degraded at the onset of G2/M phase. Ref.8
Sequence similarities	Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. WEE1 subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Cell cycle Cell division Mitosis
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	G1/S transition of mitotic cell cycle Traceable author statement. Source: Reactome G2/M transition of mitotic cell cycle Traceable author statement. Source: Reactome S phase of mitotic cell cycle Traceable author statement. Source: Reactome blood coagulation Traceable author statement. Source: Reactome cell cycle checkpoint Traceable author statement. Source: Reactome cell division Inferred from electronic annotation. Source: UniProtKB-KW mitosis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleoplasm Traceable author statement. Source: Reactome
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: InterPro non-membrane spanning protein tyrosine kinase activity Inferred from electronic annotation. Source: EC protein binding Inferred from physical interaction Ref.8. Source: IntAct protein serine/threonine kinase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BTRC	Q9Y297	2	EBI-914695,EBI-307461
FBXW11	Q9UKB1	2	EBI-914695,EBI-355189

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 646

646

Wee1-like protein kinase

PRO_0000086810

Regions

Domain

299 – 569

271

Protein kinase

Nucleotide binding

305 – 313

9

ATP By similarity

Compositional bias

9 – 12

4

Poly-Pro

Compositional bias

34 – 43

10

Poly-Glu

Sites

Active site

426

1

Proton acceptor By similarity

Metal binding

431

1

Magnesium; via carbonyl oxygen

Metal binding

463

1

Magnesium; via carbonyl oxygen

Binding site

328

1

ATP By similarity

Amino acid modifications

Modified residue

53

1

Phosphoserine; by PLK1 Ref.8

Modified residue

67

1

Phosphoserine Ref.13

Modified residue

123

1

Phosphoserine; by CDK1 Ref.8

Modified residue

127

1

Phosphoserine Ref.10 Ref.13

Modified residue

139

1

Phosphoserine Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14

Modified residue

150

1

Phosphoserine Ref.13

Modified residue

165

1

Phosphoserine Ref.10

Modified residue

173

1

Phosphothreonine Ref.11 Ref.13

Modified residue

190

1

Phosphothreonine Ref.13

Modified residue

312

1

Phosphoserine Ref.13

Modified residue

642

1

Phosphoserine; by BRSK1 and BRSK2 Ref.7 Ref.15

Natural variations

Natural variant

210

1

G → C. Ref.17
Corresponds to variant rs34412975 [ dbSNP | Ensembl ].

VAR_041302

Natural variant

472

1

S → I. Ref.17
Corresponds to variant rs56411856 [ dbSNP | Ensembl ].

VAR_041303

Experimental info

Mutagenesis

53

1

S → A: Abolishes phosphorylation by PLK1 and CDK1 and binding of the SCF(BTRC) complex, leading to stabilization of the protein; when associated with A-123. Ref.8

Mutagenesis

116 – 117

2

EE → AA: Impairs binding of the SCF(BTRC) complex.

Mutagenesis

123

1

S → A: Abolishes phosphorylation by PLK1 and CDK1 and binding of the SCF(BTRC) complex, leading to stabilization of the protein; when associated with A-53. Ref.8

Mutagenesis

328

1

K → R: Abolishes activity. Ref.6

Mutagenesis

642

1

S → A: Abolishes phosphorylation by BRSK1 and BRSK2. Ref.15

Sequence conflict

65

1

A → E in CAA43979. Ref.4

Secondary structure

1

.

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646

Helix Strand Turn

Details...

Helix

294 – 298

5

Beta strand

299 – 308

10

Beta strand

311 – 318

8

Turn

319 – 321

3

Beta strand

324 – 331

8

Helix

338 – 352

15

Beta strand

362 – 368

7

Beta strand

371 – 377

7

Helix

384 – 394

11

Helix

400 – 419

20

Helix

429 – 431

3

Beta strand

432 – 435

4

Beta strand

458 – 461

4

Helix

480 – 482

3

Helix

485 – 488

4

Helix

495 – 510

16

Beta strand

518 – 520

3

Helix

521 – 527

7

Helix

540 – 549

10

Helix

554 – 556

3

Helix

560 – 564

5

Sequences

	Sequence		Length	Mass (Da)
	P30291 [UniParc]. Last modified February 1, 1996. Version 2. Checksum: DB00623D304562A0	FASTA	646	71,597
	10 20 30 40 50 60 MSFLSRQQPP PPRRAGAACT LRQKLIFSPC SDCEEEEEEE EEEGSGHSTG EDSAFQEPDS 70 80 90 100 110 120 PLPPARSPTE PGPERRRSPG PAPGSPGELE EDLLLPGACP GADEAGGGAE GDSWEEEGFG 130 140 150 160 170 180 SSSPVKSPAA PYFLGSSFSP VRCGGPGDAS PRGCGARRAG EGRRSPRPDH PGTPPHKTFR 190 200 210 220 230 240 KLRLFDTPHT PKSLLSKARG IDSSSVKLRG SSLFMDTEKS GKREFDVRQT PQVNINPFTP 250 260 270 280 290 300 DSLLLHSSGQ CRRRKRTYWN DSCGEDMEAS DYELEDETRP AKRITITESN MKSRYTTEFH 310 320 330 340 350 360 ELEKIGSGEF GSVFKCVKRL DGCIYAIKRS KKPLAGSVDE QNALREVYAH AVLGQHSHVV 370 380 390 400 410 420 RYFSAWAEDD HMLIQNEYCN GGSLADAISE NYRIMSYFKE AELKDLLLQV GRGLRYIHSM 430 440 450 460 470 480 SLVHMDIKPS NIFISRTSIP NAASEEGDED DWASNKVMFK IGDLGHVTRI SSPQVEEGDS 490 500 510 520 530 540 RFLANEVLQE NYTHLPKADI FALALTVVCA AGAEPLPRNG DQWHEIRQGR LPRIPQVLSQ 550 560 570 580 590 600 EFTELLKVMI HPDPERRPSA MALVKHSVLL SASRKSAEQL RIELNAEKFK NSLLQKELKK 610 620 630 640 AQMAKAAAEE RALFTDRMAT RSTTQSNRTS RLIGKKMNRS VSLTIY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle." Watanabe N., Broome M., Hunter T. EMBO J. 14:1878-1891(1995) [PubMed: 7743995] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION.
[2]	"Comparative architectural aspects of regions of conserved synteny on human chromosome 11p15.3 and mouse chromosome 7 (including genes WEE1 and LMO1)." Cichutek A., Brueckmann T., Seipel B., Hauser H., Schlaubitz S., Prawitt D., Hankeln T., Schmidt E.R., Winterpacht A., Zabel B.U. Cytogenet. Cell Genet. 93:277-283(2001) [PubMed: 11528126] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Blood.
[3]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Igarashi M. Submitted (JUN-1994) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-214.
[5]	"Wee1(+)-like gene in human cells." Igarashi M., Nagata A., Jinno S., Suto K., Okayama H. Nature 353:80-83(1991) [PubMed: 1840647] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 215-646.
[6]	"Human Wee1 kinase inhibits cell division by phosphorylating p34cdc2 exclusively on Tyr15." McGowan C.H., Russell P. EMBO J. 12:75-85(1993) [PubMed: 8428596] [Abstract] Cited for: CHARACTERIZATION, MUTAGENESIS OF LYS-328.
[7]	"Human SAD1 kinase is involved in UV-induced DNA damage checkpoint function." Lu R., Niida H., Nakanishi M. J. Biol. Chem. 279:31164-31170(2004) [PubMed: 15150265] [Abstract] Cited for: PHOSPHORYLATION AT SER-642. Tissue: Testis.
[8]	"M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCFbeta-TrCP." Watanabe N., Arai H., Nishihara Y., Taniguchi M., Watanabe N., Hunter T., Osada H. Proc. Natl. Acad. Sci. U.S.A. 101:4419-4424(2004) [PubMed: 15070733] [Abstract] Cited for: PHOSPHORYLATION AT SER-53 AND SER-123, UBIQUITINATION, MUTAGENESIS OF SER-53; 116-GLU-GLU-117 AND SER-123.
[9]	"Large-scale characterization of HeLa cell nuclear phosphoproteins." Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J., Li J., Cohn M.A., Cantley L.C., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004) [PubMed: 15302935] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-139, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[10]	"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-127; SER-139 AND SER-165, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry." Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R., Keri G., Wehland J., Daub H. Mol. Cell. Proteomics 6:537-547(2007) [PubMed: 17192257] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-139 AND THR-173, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[12]	"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis." Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III J. Proteome Res. 7:1346-1351(2008) [PubMed: 18220336] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-139, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[13]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-67; SER-127; SER-139; SER-150; THR-173; THR-190 AND SER-312, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[14]	"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-139, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[15]	"Persistence of the cell-cycle checkpoint kinase Wee1 in SadA- and SadB-deficient neurons disrupts neuronal polarity." Muller M., Lutter D., Puschel A.W. J. Cell Sci. 123:286-294(2010) [PubMed: 20026642] [Abstract] Cited for: PHOSPHORYLATION AT SER-642, MUTAGENESIS OF SER-642.
[16]	"Structure and inhibition of the human cell cycle checkpoint kinase, Wee1A kinase: an atypical tyrosine kinase with a key role in CDK1 regulation." Squire C.J., Dickson J.M., Ivanovic I., Baker E.N. Structure 13:541-550(2005) [PubMed: 15837193] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.81 ANGSTROMS) OF 291-575 IN COMPLEX WITH MAGNESIUM AND AN INHIBITOR.
[17]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] CYS-210 AND ILE-472.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U10564 mRNA. Translation: AAB60401.1.
AJ277546 Genomic DNA. Translation: CAC14173.1.
CH471064 Genomic DNA. Translation: EAW68586.1.
CH471064 Genomic DNA. Translation: EAW68588.1.
X62048 mRNA. Translation: CAA43979.1.

IPI

IPI00025830.

PIR

S55048.

RefSeq

NP_003381.1. NM_003390.3.

UniGene

Hs.249441.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1X8B	X-ray	1.81	A	291-575	[»]
2IN6	X-ray	1.90	A	291-575	[»]
2IO6	X-ray	2.20	A	291-575	[»]
2Z2W	X-ray	2.22	A	291-575	[»]
3BI6	X-ray	2.20	A	291-575	[»]
3BIZ	X-ray	2.20	A	291-575	[»]
3CQE	X-ray	2.50	A	291-575	[»]
3CR0	X-ray	2.30	A	291-575	[»]

ProteinModelPortal

P30291.

SMR

P30291. Positions 291-569.

ModBase

Search...

Protein-protein interaction databases

IntAct

P30291. 5 interactions.

MINT

MINT-129561.

STRING

P30291.

PTM databases

PhosphoSite

P30291.

Polymorphism databases

DMDM

1351419.

Proteomic databases

PRIDE

P30291.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000450114; ENSP00000402084; ENSG00000166483.

GeneID

7465.

KEGG

hsa:7465.

UCSC

uc001mhs.1. human.

Organism-specific databases

CTD

7465.

GeneCards

GC11P009550.

H-InvDB

HIX0026153.

HGNC

HGNC:12761. WEE1.

HPA

CAB004619.

MIM

193525. gene.

neXtProt

NX_P30291.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG19905.

HOGENOM

HBG713564.

HOVERGEN

HBG005050.

InParanoid

P30291.

OMA

RTYWNDS.

OrthoDB

EOG44TP7J.

PhylomeDB

P30291.

Enzyme and pathway databases

BRENDA

2.7.10.2. 2681.

Reactome

REACT_152. Cell Cycle, Mitotic.
REACT_1538. Cell Cycle Checkpoints.
REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

P30291.

Bgee

P30291.

CleanEx

HS_WEE1.

Genevestigator

P30291.

GermOnline

ENSG00000166483. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_kinase-like_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR017164. Wee1-like_protein_kinase.
[Graphical view]

KO

K06632.

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

PIRSF

PIRSF037281. Wee1-like_protein_kinase. 1 hit.

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

29236.

PMAP-CutDB

P30291.

SOURCE

Search...

Entry information

Entry name

WEE1_HUMAN

Accession

Primary (citable) accession number: P30291
Secondary accession number(s): D3DQV0

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	February 1, 1996
Last modified:	January 25, 2012
This is version 130 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.