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Protein

Serine/threonine-protein kinase 4

Gene

Stk4

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 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2. Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on 'Ser-212' and regulates its activation and stimulates transcription of PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53 dependent transcription and apoptosis upon DNA damage. Acts as an inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses its activity by intersecting with PKB/AKT1 signaling and antagonizing formation of AR-chromatin complexes (By similarity).By similarity1 Publication

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-183. Activated by RASSF1 which acts by preventing its dephosphorylation (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei59ATPPROSITE-ProRule annotation1
Active sitei149Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi36 – 44ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

  • apoptotic process Source: UniProtKB
  • cell differentiation involved in embryonic placenta development Source: MGI
  • cell morphogenesis 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: MGI
  • keratinocyte differentiation Source: MGI
  • 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
  • patterning of blood vessels Source: MGI
  • peptidyl-serine phosphorylation Source: MGI
  • positive regulation of apoptotic process Source: MGI
  • positive regulation of extrinsic apoptotic signaling pathway via death domain receptors Source: MGI
  • positive regulation of fat cell differentiation Source: MGI
  • positive regulation of peptidyl-serine phosphorylation Source: MGI
  • positive regulation of protein binding Source: MGI
  • positive regulation of protein phosphorylation Source: MGI
  • primitive hemopoiesis Source: MGI
  • protein autophosphorylation Source: MGI
  • protein phosphorylation Source: UniProtKB
  • protein stabilization Source: MGI
  • regulation of cell differentiation involved in embryonic placenta development Source: MGI
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

ReactomeiR-MMU-2028269. Signaling by Hippo.

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase 4 (EC:2.7.11.1)
Alternative name(s):
Mammalian STE20-like protein kinase 1
Short name:
MST-1
STE20-like kinase MST1
Cleaved into the following 2 chains:
Gene namesi
Name:Stk4
Synonyms:Mst1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 2

Organism-specific databases

MGIiMGI:1929004. Stk4.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity

  • Note: The caspase-cleaved form cycles between nucleus and cytoplasm.By similarity

GO - Cellular componenti

  • cytoplasm Source: MGI
  • nucleus Source: MGI
  • protein complex Source: MGI
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)DescriptionActionsGraphical viewLength
ChainiPRO_00002466271 – 487Serine/threonine-protein kinase 4Add BLAST487
ChainiPRO_00004137411 – 326Serine/threonine-protein kinase 4 37kDa subunitAdd BLAST326
ChainiPRO_0000413742327 – 487Serine/threonine-protein kinase 4 18kDa subunitAdd BLAST161

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineBy similarity1
Modified residuei3PhosphothreonineBy similarity1
Modified residuei120Phosphothreonine; by PKB/AKT1By similarity1
Modified residuei183Phosphothreonine; by autocatalysisBy similarity1
Modified residuei265PhosphoserineBy similarity1
Modified residuei320PhosphoserineCombined sources1
Modified residuei340PhosphothreonineBy similarity1
Modified residuei367PhosphothreonineBy similarity1
Modified residuei387Phosphothreonine; by PKB/AKT1By similarity1
Modified residuei410PhosphoserineBy similarity1
Modified residuei433PhosphotyrosineCombined sources1

Post-translational modificationi

Autophosphorylated on serine and threonine residues. Phosphorylation at Thr-120 and Thr-387 by PKB/AKT1, leads to inhibition of its: kinase activity, nuclear translocation and autophosphorylation at Thr-183. It also diminishes its cleavage by caspases and its ability to phosphorylate FOXO3 (By similarity).By similarity
Proteolytically cleaved by caspase-3 during apoptosis at Asp-326 resulting in a 37 kDa form. Proteolytic cleavage results in kinase activation and nuclear translocation of the truncated form (MST1/N).1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei326 – 327Cleavage; by caspase-32

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ9JI11.
MaxQBiQ9JI11.
PaxDbiQ9JI11.
PeptideAtlasiQ9JI11.
PRIDEiQ9JI11.

PTM databases

iPTMnetiQ9JI11.
PhosphoSitePlusiQ9JI11.

Expressioni

Gene expression databases

BgeeiENSMUSG00000018209.
CleanExiMM_STK4.
ExpressionAtlasiQ9JI11. baseline and differential.
GenevisibleiQ9JI11. MM.

Interactioni

Subunit structurei

Homodimer; mediated via the coiled-coil region. Interacts with NORE1, which inhibits autoactivation. Interacts with and stabilizes SAV1. Interacts with RASSF1. Interacts with FOXO3. Interacts with RASSF2 (via SARAH domain). Interacts with AR, PKB/AKT1, TNNI3 and SIRT1 (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Rassf5Q5EBH13EBI-1181352,EBI-960530

GO - Molecular functioni

Protein-protein interaction databases

BioGridi208405. 2 interactors.
IntActiQ9JI11. 9 interactors.
STRINGi10090.ENSMUSP00000018353.

Structurei

3D structure databases

ProteinModelPortaliQ9JI11.
SMRiQ9JI11.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini30 – 281Protein kinasePROSITE-ProRule annotationAdd BLAST252
Domaini433 – 480SARAHPROSITE-ProRule annotationAdd BLAST48

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili289 – 311Sequence analysisAdd BLAST23

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi373 – 378Poly-Glu6

Sequence similaritiesi

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

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG0201. Eukaryota.
ENOG410XP9G. LUCA.
GeneTreeiENSGT00810000125395.
HOGENOMiHOG000234203.
HOVERGENiHBG108518.
InParanoidiQ9JI11.
KOiK04411.
OMAiAMINEAM.
OrthoDBiEOG091G065P.
PhylomeDBiQ9JI11.
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.
[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]

Sequencei

Sequence statusi: Complete.

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

Q9JI11-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
METVQLRNPP RRQLKKLDED SLTKQPEEVF DVLEKLGEGS YGSVYKAIHK
60 70 80 90 100
ETGQIVAIKQ VPVESDLQEI IKEISIMQQC DSPHVVKYYG SYFKNTDLWI
110 120 130 140 150
VMEYCGAGSV SDIIRLRNKT LTEDEIATIL QSTLKGLEYL HFMRKIHRDI
160 170 180 190 200
KAGNILLNTE GHAKLADFGV AGQLTDTMAK RNTVIGTPFW MAPEVIQEIG
210 220 230 240 250
YNCVADIWSL GITAIEMAEG KPPYADIHPM RAIFMIPTNP PPTFRKPELW
260 270 280 290 300
SDNFMDFVKQ CLVKSPEQRA TATQLLQHPF VKSAKGVSIL RDLINEAMDV
310 320 330 340 350
KLKRQEAQQR EVDQDDEENS EEDEMDSGTM VRAAGDEMGT VRVASTMSGG
360 370 380 390 400
ANTMIEHGDT LPSQLGTMVI NTEDEEEEGT MKRRDETMQP AKPSFLEYFE
410 420 430 440 450
QKEKENQINS FGKNVSGSLK NSSDWKIPQD GDYEFLKSWT VEDLQKRLLA
460 470 480
LDPMMEQEME EIRQKYRSKR QPILDAIEAK KRRQQNF
Length:487
Mass (Da):55,541
Last modified:October 1, 2000 - v1
Checksum:iA21E9519AD209C40
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF271360 mRNA. Translation: AAF75789.1.
AK028838 mRNA. Translation: BAC26147.1.
BC054521 mRNA. Translation: AAH54521.1.
CCDSiCCDS17021.1.
RefSeqiNP_067395.1. NM_021420.3.
UniGeneiMm.234472.

Genome annotation databases

EnsembliENSMUST00000018353; ENSMUSP00000018353; ENSMUSG00000018209.
GeneIDi58231.
KEGGimmu:58231.
UCSCiuc008ntt.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF271360 mRNA. Translation: AAF75789.1.
AK028838 mRNA. Translation: BAC26147.1.
BC054521 mRNA. Translation: AAH54521.1.
CCDSiCCDS17021.1.
RefSeqiNP_067395.1. NM_021420.3.
UniGeneiMm.234472.

3D structure databases

ProteinModelPortaliQ9JI11.
SMRiQ9JI11.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi208405. 2 interactors.
IntActiQ9JI11. 9 interactors.
STRINGi10090.ENSMUSP00000018353.

PTM databases

iPTMnetiQ9JI11.
PhosphoSitePlusiQ9JI11.

Proteomic databases

EPDiQ9JI11.
MaxQBiQ9JI11.
PaxDbiQ9JI11.
PeptideAtlasiQ9JI11.
PRIDEiQ9JI11.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000018353; ENSMUSP00000018353; ENSMUSG00000018209.
GeneIDi58231.
KEGGimmu:58231.
UCSCiuc008ntt.1. mouse.

Organism-specific databases

CTDi6789.
MGIiMGI:1929004. Stk4.

Phylogenomic databases

eggNOGiKOG0201. Eukaryota.
ENOG410XP9G. LUCA.
GeneTreeiENSGT00810000125395.
HOGENOMiHOG000234203.
HOVERGENiHBG108518.
InParanoidiQ9JI11.
KOiK04411.
OMAiAMINEAM.
OrthoDBiEOG091G065P.
PhylomeDBiQ9JI11.
TreeFamiTF354217.

Enzyme and pathway databases

ReactomeiR-MMU-2028269. Signaling by Hippo.

Miscellaneous databases

PROiQ9JI11.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000018209.
CleanExiMM_STK4.
ExpressionAtlasiQ9JI11. baseline and differential.
GenevisibleiQ9JI11. 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.
[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...

Entry informationi

Entry nameiSTK4_MOUSE
AccessioniPrimary (citable) accession number: Q9JI11
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 25, 2006
Last sequence update: October 1, 2000
Last modified: November 30, 2016
This is version 141 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

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 one 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.