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Protein

Serine/threonine-protein kinase 3

Gene

Stk3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1. Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosomes, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38 (By similarity).By similarity

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+By similarity

Enzyme regulationi

Inhibited by the C-terminal non-catalytic region. Activated by caspase-cleavage. Full activation also requires homodimerization and autophosphorylation of Thr-180, which are inhibited by the proto-oncogene product RAF1. Activated by RASSF1 which acts by preventing its dephosphorylation (By similarity).By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei56 – 561ATPPROSITE-ProRule annotation
Active sitei146 – 1461Proton acceptorPROSITE-ProRule annotation
Sitei322 – 3232Cleavage; by caspase-3

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi33 – 419ATPPROSITE-ProRule annotation

GO - Molecular functioni

GO - Biological processi

  • activation of MAPKK activity Source: GO_Central
  • cell differentiation involved in embryonic placenta development Source: MGI
  • central nervous system development Source: MGI
  • endocardium development Source: MGI
  • hepatocyte apoptotic process Source: MGI
  • hippo signaling Source: UniProtKB
  • intracellular signal transduction Source: UniProtKB
  • MAPK cascade Source: GOC
  • negative regulation of canonical Wnt signaling pathway Source: MGI
  • negative regulation of cell proliferation Source: MGI
  • negative regulation of organ growth Source: MGI
  • neural tube formation Source: MGI
  • positive regulation of apoptotic process Source: UniProtKB
  • positive regulation of extrinsic apoptotic signaling pathway via death domain receptors Source: MGI
  • positive regulation of fat cell differentiation Source: MGI
  • positive regulation of JNK cascade Source: MGI
  • positive regulation of protein binding Source: MGI
  • positive regulation of protein kinase B signaling Source: MGI
  • positive regulation of sequence-specific DNA binding transcription factor activity Source: MGI
  • primitive hemopoiesis Source: MGI
  • protein phosphorylation Source: UniProtKB
  • protein stabilization Source: MGI
  • regulation of cell differentiation involved in embryonic placenta development Source: MGI
  • regulation of mitotic cell cycle Source: GO_Central
  • signal transduction by protein phosphorylation Source: GO_Central
  • stress-activated protein kinase signaling cascade Source: GO_Central
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Apoptosis

Keywords - Ligandi

ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiREACT_301726. Signaling by Hippo.

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase 3 (EC:2.7.11.1)
Alternative name(s):
Mammalian STE20-like protein kinase 2
Short name:
MST-2
STE20-like kinase MST2
Cleaved into the following 2 chains:
Gene namesi
Name:Stk3
Synonyms:Mess1, Mst2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 15

Organism-specific databases

MGIiMGI:1928487. Stk3.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity

  • Note: The caspase-cleaved form cycles between nucleus and cytoplasm. Phosphorylation at Thr-117 leads to inhibition of nuclear translocation (By similarity).By similarity

GO - Cellular componenti

  • cytoplasm Source: MGI
  • nucleus Source: GO_Central
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice show progressive hepatomegaly with a 2-fold increase in liver mass relative to total body mass at 1 month of age and a 3-fold increase by 3 months of age.1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 497497Serine/threonine-protein kinase 3PRO_0000086690Add
BLAST
Chaini1 – 322322Serine/threonine-protein kinase 3 36kDa subunitPRO_0000413715Add
BLAST
Chaini323 – 497175Serine/threonine-protein kinase 3 20kDa subunitPRO_0000413716Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei1 – 11N-acetylmethionineBy similarity
Modified residuei15 – 151PhosphoserineBy similarity
Modified residuei117 – 1171Phosphothreonine; by PKB/AKT1By similarity
Modified residuei180 – 1801Phosphothreonine; by autocatalysisBy similarity
Modified residuei316 – 3161Phosphoserine2 Publications
Modified residuei336 – 3361PhosphothreonineBy similarity
Modified residuei390 – 3901Phosphothreonine; by PKB/AKT1By similarity
Modified residuei450 – 4501PhosphoserineBy similarity

Post-translational modificationi

Phosphorylation at Thr-117 and Thr-390 by PKB/AKT1, leads to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation, and increase in its binding to RAF1.By similarity
Proteolytically cleaved by caspase-3 during apoptosis. Proteolytic cleavage results in kinase activation and nuclear translocation of the truncated form (MST1/N).1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiQ9JI10.
PaxDbiQ9JI10.
PRIDEiQ9JI10.

PTM databases

PhosphoSiteiQ9JI10.

Expressioni

Gene expression databases

BgeeiQ9JI10.
CleanExiMM_STK3.
ExpressionAtlasiQ9JI10. baseline and differential.
GenevisibleiQ9JI10. MM.

Interactioni

Subunit structurei

Homodimer; mediated via the coiled-coil region. Interacts with NORE1, which inhibits autoactivation. Interacts with and stabilizes SAV1. Interacts with RAF1, which prevents dimerization and phosphorylation. Interacts with RASSF1. Interacts (via SARAH domain) with NEK2 (By similarity). Interacts with ESR1 only in the presence of SAV1. Interacts with PKB/AKT1. Forms a tripartite complex with MOBKL1B and STK38. Interacts with RASSF2 (via SARAH domain) (By similarity).By similarity

Protein-protein interaction databases

BioGridi207869. 1 interaction.
IntActiQ9JI10. 1 interaction.
STRINGi10090.ENSMUSP00000018476.

Structurei

3D structure databases

ProteinModelPortaliQ9JI10.
SMRiQ9JI10. Positions 10-302, 443-494.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini27 – 278252Protein kinasePROSITE-ProRule annotationAdd
BLAST
Domaini443 – 49048SARAHPROSITE-ProRule annotationAdd
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili287 – 32842Sequence AnalysisAdd
BLAST
Coiled coili366 – 38722Sequence AnalysisAdd
BLAST
Coiled coili448 – 47932Sequence AnalysisAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi293 – 38189Glu-richAdd
BLAST
Compositional biasi308 – 3147Poly-Glu
Compositional biasi370 – 38112Poly-GluAdd
BLAST

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 SARAH domain.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00800000124019.
HOGENOMiHOG000234203.
HOVERGENiHBG108518.
InParanoidiQ9JI10.
KOiK04412.
OMAiXDEDELD.
OrthoDBiEOG7TF79T.
PhylomeDBiQ9JI10.
TreeFamiTF354217.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR024205. Mst1_SARAH_domain.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR011524. SARAH_dom.
IPR002290. Ser/Thr_dual-sp_kinase.
[Graphical view]
PfamiPF11629. Mst1_SARAH. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS50951. SARAH. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9JI10-1) [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
MEQPPASKSK LKKLSEDSLT KQPEEVFDVL EKLGEGSYGS VFKAIHKESG
60 70 80 90 100
QVVAIKQVPV ESDLQEIIKE ISIMQQCDSP YVVKYYGSYF KNTDLWIVME
110 120 130 140 150
YCGAGSVSDI IRLRNKTLTE DEIATILKST LKGLEYLHFM RKIHRDIKAG
160 170 180 190 200
NILLNTEGHA KLADFGVAGQ LTDTMAKRNT VIGTPFWMAP EVIQEIGYNC
210 220 230 240 250
VADIWSLGIT SIEMAEGKPP YADIHPMRAI FMIPTNPPPT FRKPELWSDD
260 270 280 290 300
FTDFVKKCLV KSPEQRATAT QLLQHPFIKN AKPVSILRDL IAEAMEIKAK
310 320 330 340 350
RHEEQQRELE EEEENSDEDE LDSHTMVKTS SESVGTMRAT STMSEGAQTM
360 370 380 390 400
IEHNSTMLES DLGTMVINSE EEEEEEEEEE EDGTMKRNAT SPQVQRPSFM
410 420 430 440 450
DYFDKQDFKN KSHENCDQSM REPGPMSNSV FPDNWRVPQD GDFDFLKNLS
460 470 480 490
LEELQMRLKA LDPMMEREIE ELHQRYSAKR QPILDAMDAK KRRQQNF
Length:497
Mass (Da):56,855
Last modified:October 1, 2000 - v1
Checksum:i9CDD365437581665
GO
Isoform 2 (identifier: Q9JI10-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     9-78: Missing.

Note: No experimental confirmation available.
Show »
Length:427
Mass (Da):49,067
Checksum:i556176AE5A26F79E
GO

Sequence cautioni

The sequence AAA75300.1 differs from that shown. Reason: Frameshift at position 432. Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei9 – 7870Missing in isoform 2. 1 PublicationVSP_020047Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF271361 mRNA. Translation: AAF75790.1.
U28726 mRNA. Translation: AAA75300.1. Frameshift.
AY058922 mRNA. Translation: AAL29682.1.
BC037440 mRNA. Translation: AAH37440.1.
BC049123 mRNA. Translation: AAH49123.2.
CCDSiCCDS37059.1. [Q9JI10-1]
RefSeqiNP_062609.2. NM_019635.2. [Q9JI10-1]
UniGeneiMm.262330.

Genome annotation databases

EnsembliENSMUST00000018476; ENSMUSP00000018476; ENSMUSG00000022329. [Q9JI10-1]
ENSMUST00000067033; ENSMUSP00000064225; ENSMUSG00000022329. [Q9JI10-2]
GeneIDi56274.
KEGGimmu:56274.
UCSCiuc007vlz.1. mouse. [Q9JI10-1]
uc011zrz.1. mouse. [Q9JI10-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF271361 mRNA. Translation: AAF75790.1.
U28726 mRNA. Translation: AAA75300.1. Frameshift.
AY058922 mRNA. Translation: AAL29682.1.
BC037440 mRNA. Translation: AAH37440.1.
BC049123 mRNA. Translation: AAH49123.2.
CCDSiCCDS37059.1. [Q9JI10-1]
RefSeqiNP_062609.2. NM_019635.2. [Q9JI10-1]
UniGeneiMm.262330.

3D structure databases

ProteinModelPortaliQ9JI10.
SMRiQ9JI10. Positions 10-302, 443-494.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi207869. 1 interaction.
IntActiQ9JI10. 1 interaction.
STRINGi10090.ENSMUSP00000018476.

Chemistry

BindingDBiQ9JI10.
ChEMBLiCHEMBL4310.

PTM databases

PhosphoSiteiQ9JI10.

Proteomic databases

MaxQBiQ9JI10.
PaxDbiQ9JI10.
PRIDEiQ9JI10.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000018476; ENSMUSP00000018476; ENSMUSG00000022329. [Q9JI10-1]
ENSMUST00000067033; ENSMUSP00000064225; ENSMUSG00000022329. [Q9JI10-2]
GeneIDi56274.
KEGGimmu:56274.
UCSCiuc007vlz.1. mouse. [Q9JI10-1]
uc011zrz.1. mouse. [Q9JI10-2]

Organism-specific databases

CTDi6788.
MGIiMGI:1928487. Stk3.

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00800000124019.
HOGENOMiHOG000234203.
HOVERGENiHBG108518.
InParanoidiQ9JI10.
KOiK04412.
OMAiXDEDELD.
OrthoDBiEOG7TF79T.
PhylomeDBiQ9JI10.
TreeFamiTF354217.

Enzyme and pathway databases

ReactomeiREACT_301726. Signaling by Hippo.

Miscellaneous databases

ChiTaRSiStk3. mouse.
NextBioi312160.
PROiQ9JI10.
SOURCEiSearch...

Gene expression databases

BgeeiQ9JI10.
CleanExiMM_STK3.
ExpressionAtlasiQ9JI10. baseline and differential.
GenevisibleiQ9JI10. MM.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR024205. Mst1_SARAH_domain.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR011524. SARAH_dom.
IPR002290. Ser/Thr_dual-sp_kinase.
[Graphical view]
PfamiPF11629. Mst1_SARAH. 1 hit.
PF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS50951. SARAH. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "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] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEOLYTIC PROCESSING.
    Strain: BALB/c.
  2. Han J.
    Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    Tissue: Liver.
  3. "Molecular cloning and characterization of mouse MST2 kinase from olfactory receptor neurons."
    de las Heras R., Mackay-Sim A., Bushell G.R.
    Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    Tissue: Olfactory epithelium.
  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] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
    Strain: C57BL/6 and FVB/N.
    Tissue: Brain and Mammary gland.
  5. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-316, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Liver.
  6. "The phagosomal proteome in interferon-gamma-activated macrophages."
    Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P.
    Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-316, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  7. "Large scale localization of protein phosphorylation by use of electron capture dissociation mass spectrometry."
    Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.
    Mol. Cell. Proteomics 8:904-912(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Embryonic fibroblast.
  8. "Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver."
    Lu L., Li Y., Kim S.M., Bossuyt W., Liu P., Qiu Q., Wang Y., Halder G., Finegold M.J., Lee J.S., Johnson R.L.
    Proc. Natl. Acad. Sci. U.S.A. 107:1437-1442(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.

Entry informationi

Entry nameiSTK3_MOUSE
AccessioniPrimary (citable) accession number: Q9JI10
Secondary accession number(s): Q60877, Q80UG4, Q8CI58
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 26, 2004
Last sequence update: October 1, 2000
Last modified: July 22, 2015
This is version 129 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.