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Reviewed, UniProtKB/Swiss-Prot Q13043 (STK4_HUMAN)

Last modified June 16, 2009. Version 96. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Serine/threonine-protein kinase 4
    EC=2.7.11.1
Alternative name(s):
    STE20-like kinase MST1
      Short name=MST-1
    Mammalian STE20-like protein kinase 1
    Serine/threonine-protein kinase Krs-2
Gene names
Name: STK4
Synonyms: MST1
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length487 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Phosphorylates 'Ser-14' of histone H2B during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Ref.2 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium.

Enzyme regulation

Inhibited by the C-terminal non-catalytic region. Activated by caspase-cleavage. Full activation also requires homodimerization and autophosphorylation of Thr-183. Ref.6 Ref.10

Subunit structure

Homodimer; mediated via the coiled-coil region. Interacts with NORE1, which inhibits autoactivation. Interacts with and stabilizes SAV1. Interacts with RASSF1, which leads to enzyme activation. Interacts with FOXO3. Ref.6 Ref.10 Ref.11 Ref.12 Ref.13

Subcellular location

Cytoplasm. Nucleus. Note: The caspase-cleaved form cycles between the nucleus and cytoplasm. Ref.7 Ref.8

Tissue specificity

Ubiquitously expressed.

Post-translational modification

Autophosphorylated on serine and threonine residues. Ref.9 Ref.10 Ref.14 Ref.15 Ref.16

Sequence similarities

Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.

Contains 1 protein kinase domain.

Contains 1 SARAH domain.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q13043-1)

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.
Isoform 2 (identifier: Q13043-2)

The sequence of this isoform differs from the canonical sequence as follows:
     436-462: LKSWTVEDLQKRLLALDPMMEQEIEEI → KTSQEQQSGKDICIQNCQGNLLCRYAF
     463-487: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 487487Serine/threonine-protein kinase 4
PRO_0000086691

Regions

Domain30 – 281252Protein kinase
Domain433 – 48048SARAH
Nucleotide binding36 – 449ATP By similarity
Coiled coil290 – 31021 Potential
Compositional bias373 – 3786Poly-Glu

Sites

Active site1491Proton acceptor By similarity
Binding site591ATP
Site326 – 3272Cleavage; by caspase-3
Site349 – 3502Cleavage; by caspase-3

Amino acid modifications

Modified residue11N-acetylmethionine Ref.5
Modified residue1831Phosphothreonine; by autocatalysis Ref.10
Modified residue2651Phosphoserine Ref.15
Modified residue3201Phosphoserine Ref.15 Ref.16
Modified residue3401Phosphothreonine Ref.15
Modified residue4101Phosphoserine Ref.15
Modified residue4331Phosphotyrosine Ref.14
Modified residue4381Phosphoserine Ref.15

Natural variations

Alternative sequence436 – 46227LKSWT…EIEEI → KTSQEQQSGKDICIQNCQGN LLCRYAF in isoform 2.
VSP_019851
Alternative sequence463 – 48725Missing in isoform 2.
VSP_019852
Natural variant1621H → N Ref.18
VAR_041123
Natural variant3101R → Q: dbSNP rs35447878. Ref.18
VAR_041124
Natural variant3121V → M: dbSNP rs17420378. Ref.18 Ref.1
VAR_027040
Natural variant3551I → T: dbSNP rs35944046. Ref.18
VAR_041125
Natural variant4161P → L: dbSNP rs33963346. Ref.18
VAR_041126

Experimental info

Mutagenesis591K → R: Loss of activity. Ref.10 Ref.13
Mutagenesis1751T → A: No effect on activity. Ref.10
Mutagenesis1771T → A: No effect on activity. Ref.10
Mutagenesis1831T → A: Loss of activity. Ref.10
Mutagenesis3261D → N: Resistant to proteolytic cleavage by caspase during apoptosis; when associated with N-349. Ref.7
Mutagenesis3491D → N: Resistant to proteolytic cleavage by caspase during apoptosis; when associated with N-326. Ref.7
Mutagenesis4441L → P: Loss of homodimerization, activation, and autophosphorylation. Ref.10
Sequence conflict2221P → R in AAA83254. Ref.1

Secondary structure

................................................. 487
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified February 21, 2001. Version 2.
Checksum: 150758EBC5F77D5C

FASTA48755,630
        10         20         30         40         50         60 
METVQLRNPP RRQLKKLDED SLTKQPEEVF DVLEKLGEGS YGSVYKAIHK ETGQIVAIKQ 

        70         80         90        100        110        120 
VPVESDLQEI IKEISIMQQC DSPHVVKYYG SYFKNTDLWI VMEYCGAGSV SDIIRLRNKT 

       130        140        150        160        170        180 
LTEDEIATIL QSTLKGLEYL HFMRKIHRDI KAGNILLNTE GHAKLADFGV AGQLTDTMAK 

       190        200        210        220        230        240 
RNTVIGTPFW MAPEVIQEIG YNCVADIWSL GITAIEMAEG KPPYADIHPM RAIFMIPTNP 

       250        260        270        280        290        300 
PPTFRKPELW SDNFTDFVKQ CLVKSPEQRA TATQLLQHPF VRSAKGVSIL RDLINEAMDV 

       310        320        330        340        350        360 
KLKRQESQQR EVDQDDEENS EEDEMDSGTM VRAVGDEMGT VRVASTMTDG ANTMIEHDDT 

       370        380        390        400        410        420 
LPSQLGTMVI NAEDEEEEGT MKRRDETMQP AKPSFLEYFE QKEKENQINS FGKSVPGPLK 

       430        440        450        460        470        480 
NSSDWKIPQD GDYEFLKSWT VEDLQKRLLA LDPMMEQEIE EIRQKYQSKR QPILDAIEAK 


KRRQQNF 

« Hide

Isoform 2.

Checksum: 9CFFF2D1FBC316E8
Show »

FASTA46252,335

References

« Hide 'large scale' references
[1]"Cloning and characterization of a human protein kinase with homology to Ste20."
Creasy C.L., Chernoff J.
J. Biol. Chem. 270:21695-21700(1995) [PubMed: 7665586] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT MET-312.
[2]"Newly identified stress-responsive protein kinases, Krs-1 and Krs-2."
Taylor L.K., Wang H.C., Erikson R.L.
Proc. Natl. Acad. Sci. U.S.A. 93:10099-10104(1996) [PubMed: 8816758] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION.
[3]"The DNA sequence and comparative analysis of human chromosome 20."
Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. expand/collapse author list , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.
Nature 414:865-871(2001) [PubMed: 11780052] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"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].
Tissue: Bone, Brain and Liver.
[5]Bienvenut W.V., Matallanas D., Cooper W.N., Kolch W.
Submitted (JUL-2007) to UniProtKB
Cited for: PROTEIN SEQUENCE OF 1-7; 16-94; 118-144; 152-181; 232-259; 270-282; 292-301; 333-342; 384-402; 405-413; 421-465 AND 470-481, ACETYLATION AT MET-1, MASS SPECTROMETRY.
Tissue: Mammary carcinoma.
[6]"The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain."
Creasy C.L., Ambrose D.M., Chernoff J.
J. Biol. Chem. 271:21049-21053(1996) [PubMed: 8702870] [Abstract]
Cited for: FUNCTION, HOMODIMERIZATION, ENZYME REGULATION.
[7]"MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation."
Lee K.-K., Ohyama T., Yajima N., Tsubuki S., Yonehara S.
J. Biol. Chem. 276:19276-19285(2001) [PubMed: 11278283] [Abstract]
Cited for: SUBCELLULAR LOCATION, FUNCTION, CLEAVAGE BY CASPASE, MUTAGENESIS OF ASP-326 AND ASP-349.
[8]"Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation."
Ura S., Masuyama N., Graves J.D., Gotoh Y.
Proc. Natl. Acad. Sci. U.S.A. 98:10148-10153(2001) [PubMed: 11517310] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[9]"Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase."
Cheung W.L., Ajiro K., Samejima K., Kloc M., Cheung P., Mizzen C.A., Beeser A., Etkin L.D., Chernoff J., Earnshaw W.C., Allis C.D.
Cell 113:507-517(2003) [PubMed: 12757711] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF HISTONE H2B.
[10]"Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras."
Praskova M., Khoklatchev A., Ortiz-Vega S., Avruch J.
Biochem. J. 381:453-462(2004) [PubMed: 15109305] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, HOMODIMERIZATION, PHOSPHORYLATION AT THR-183, MUTAGENESIS OF LYS-59; THR-175; THR-177; THR-183 AND LEU-444, INTERACTION WITH RASSF1 AND NORE1.
[11]"Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis."
Oh H.J., Lee K.-K., Song S.J., Jin M.S., Song M.S., Lee J.H., Im C.R., Lee J.-O., Yonehara S., Lim D.-S.
Cancer Res. 66:2562-2569(2006) [PubMed: 16510573] [Abstract]
Cited for: FUNCTION, INTERACTION WITH RASSF1.
[12]"A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span."
Lehtinen M.K., Yuan Z., Boag P.R., Yang Y., Villen J., Becker E.B.E., DiBacco S., de la Iglesia N., Gygi S.P., Blackwell T.K., Bonni A.
Cell 125:987-1001(2006) [PubMed: 16751106] [Abstract]
Cited for: FUNCTION, INTERACTION WITH FOXO3.
[13]"Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation."
Callus B.A., Verhagen A.M., Vaux D.L.
FEBS J. 273:4264-4276(2006) [PubMed: 16930133] [Abstract]
Cited for: INTERACTION WITH SAV1, FUNCTION, MUTAGENESIS OF LYS-59.
[14]"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 TYR-433, MASS SPECTROMETRY.
[15]"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-265; SER-320; THR-340; SER-410 AND SER-438, MASS SPECTROMETRY.
[16]"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-320, MASS SPECTROMETRY.
[17]Colinge J., Superti-Furga G., Bennett K.L.
Submitted (OCT-2008) to UniProtKB
Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[18]"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. expand/collapse author list , 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] ASN-162; GLN-310; MET-312; THR-355 AND LEU-416.
+Additional computationally mapped references.

Cross-references

Sequence databases

U18297 mRNA. Translation: AAA83254.1.
U60207 mRNA. Translation: AAB17262.1.
Z93016, AL109839 Genomic DNA. Translation: CAB07508.2.
AL109839, Z93016 Genomic DNA. Translation: CAI95633.1.
AL109839, Z93016 Genomic DNA. Translation: CAI95634.1.
Z93016, AL109839 Genomic DNA. Translation: CAI19815.1.
BC029511 mRNA. Translation: AAH29511.1. Sequence problems.
BC058916 mRNA. Translation: AAH58916.1. Sequence problems.
BC093768 mRNA. Translation: AAH93768.1.
IPIIPI00011488.
IPI00645585.
RefSeqNP_006273.1.
UniGeneHs.472838

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
2JO8NMR-A/B432-480[»]
3COMX-ray2.20A/B2-311[»]
ModBaseSearch...

Protein-protein interaction databases

IntActQ13043. 7 interactions.

PTM databases

PhosphoSiteQ13043.

Proteomic databases

PRIDEQ13043.

Genome annotation databases

EnsemblENSG00000101109. Homo sapiens. [Contig view]
GeneID6789.
KEGGhsa:6789.

Organism-specific databases

GeneCardsGC20P043028.
H-InvDBHIX0015851.
HGNCHGNC:11408. STK4.
HPACAB004038.
CAB004965.
HPA015270.
MIM604965. gene.
PharmGKBPA36215.
GenAtlasSearch...

Phylogenomic databases

HOVERGENQ13043.
OMAQ13043. KRRDETM.

Enzyme and pathway databases

BRENDA2.7.11.1. 247.

Gene expression databases

ArrayExpressQ13043.
BgeeQ13043.
CleanExHS_MST1.
HS_STK4.
GermOnlineENSG00000101109. Homo sapiens.

Family and domain databases

InterProIPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR011524. SARAH.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR002290. Ser_thr_pkinase.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
ProDomPD000001. Prot_kinase. 2 hits.
[Graphical view] [Entries sharing at least one domain]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. False negative.
PS50951. SARAH. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio26508.
PMAP-CutDBQ13043.
SOURCESearch...

Entry information

Entry nameSTK4_HUMAN
AccessionPrimary (citable) accession number: Q13043
Secondary accession number(s): Q15802 expand/collapse secondary AC list , Q4G156, Q5H982, Q6PD60, Q9BR32, Q9NTZ4
Entry history
Integrated into UniProtKB/Swiss-Prot: February 21, 2001
Last sequence update: February 21, 2001
Last modified: June 16, 2009
This is version 96 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

Relevant documents

Human chromosome 20

Human chromosome 20: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents