UniProtKB - Q9JI11 (STK4_MOUSE)
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Protein
Serine/threonine-protein kinase 4
Gene
Stk4
Organism
Mus musculus (Mouse)
Status
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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 59 | ATPPROSITE-ProRule annotation | 1 | |
Active sitei | 149 | Proton acceptorPROSITE-ProRule annotation | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 36 – 44 | ATPPROSITE-ProRule annotation | 9 |
GO - Molecular functioni
- ATP binding Source: MGI
- identical protein binding Source: MGI
- magnesium ion binding Source: MGI
- protein dimerization activity Source: MGI
- protein homodimerization activity Source: MGI
- protein kinase activity Source: MGI
- protein serine/threonine kinase activity Source: UniProtKB
- transcription factor binding Source: MGI
GO - Biological processi
- activation of protein kinase activity Source: GO_Central
- apoptotic process Source: UniProtKB
- branching involved in blood vessel morphogenesis Source: MGI
- 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
- 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
- positive regulation of vascular associated smooth muscle cell apoptotic process Source: Ensembl
- primitive hemopoiesis Source: MGI
- protein autophosphorylation Source: MGI
- protein phosphorylation Source: MGI
- 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
Keywordsi
Molecular function | Kinase, Serine/threonine-protein kinase, Transferase |
Biological process | Apoptosis |
Ligand | ATP-binding, Magnesium, Metal-binding, Nucleotide-binding |
Enzyme and pathway databases
Reactomei | R-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 |
Organismi | Mus musculus (Mouse) |
Taxonomic identifieri | 10090 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus |
Proteomesi |
|
Organism-specific databases
MGIi | MGI:1929004 Stk4 |
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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000246627 | 1 – 487 | Serine/threonine-protein kinase 4Add BLAST | 487 | |
ChainiPRO_0000413741 | 1 – 326 | Serine/threonine-protein kinase 4 37kDa subunitAdd BLAST | 326 | |
ChainiPRO_0000413742 | 327 – 487 | Serine/threonine-protein kinase 4 18kDa subunitAdd BLAST | 161 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 1 | N-acetylmethionineBy similarity | 1 | |
Modified residuei | 3 | PhosphothreonineBy similarity | 1 | |
Modified residuei | 183 | Phosphothreonine; by autocatalysisBy similarity | 1 | |
Modified residuei | 265 | PhosphoserineBy similarity | 1 | |
Modified residuei | 320 | PhosphoserineCombined sources | 1 | |
Modified residuei | 340 | PhosphothreonineBy similarity | 1 | |
Modified residuei | 367 | PhosphothreonineBy similarity | 1 | |
Modified residuei | 387 | Phosphothreonine; by PKB/AKT1By similarity | 1 | |
Modified residuei | 410 | PhosphoserineBy similarity | 1 | |
Modified residuei | 433 | PhosphotyrosineCombined sources | 1 |
Post-translational modificationi
Autophosphorylated on serine and threonine residues. Phosphorylation at 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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sitei | 326 – 327 | Cleavage; by caspase-3 | 2 |
Keywords - PTMi
Acetylation, PhosphoproteinProteomic databases
EPDi | Q9JI11 |
MaxQBi | Q9JI11 |
PaxDbi | Q9JI11 |
PeptideAtlasi | Q9JI11 |
PRIDEi | Q9JI11 |
PTM databases
iPTMneti | Q9JI11 |
PhosphoSitePlusi | Q9JI11 |
Expressioni
Gene expression databases
Bgeei | ENSMUSG00000018209 |
CleanExi | MM_STK4 |
ExpressionAtlasi | Q9JI11 baseline and differential |
Genevisiblei | Q9JI11 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. Interacts with MARK3 and SCRIB in the presence of DLG5 (By similarity). Interacts with DLG5 (via PDZ domain 3) (PubMed:28087714).By similarity1 Publication
Binary interactionsi
With | Entry | #Exp. | IntAct | Notes |
---|---|---|---|---|
Rassf5 | Q5EBH1 | 3 | EBI-1181352,EBI-960530 |
GO - Molecular functioni
- identical protein binding Source: MGI
- protein dimerization activity Source: MGI
- protein homodimerization activity Source: MGI
- transcription factor binding Source: MGI
Protein-protein interaction databases
BioGridi | 2084053 interactors. |
IntActi | Q9JI11 9 interactors. |
MINTi | Q9JI11 |
STRINGi | 10090.ENSMUSP00000018353 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 30 – 281 | Protein kinasePROSITE-ProRule annotationAdd BLAST | 252 | |
Domaini | 433 – 480 | SARAHPROSITE-ProRule annotationAdd BLAST | 48 |
Coiled coil
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Coiled coili | 289 – 311 | Sequence analysisAdd BLAST | 23 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 373 – 378 | Poly-Glu | 6 |
Sequence similaritiesi
Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.Curated
Keywords - Domaini
Coiled coilPhylogenomic databases
eggNOGi | KOG0201 Eukaryota ENOG410XP9G LUCA |
GeneTreei | ENSGT00900000140794 |
HOGENOMi | HOG000234203 |
HOVERGENi | HBG108518 |
InParanoidi | Q9JI11 |
KOi | K04411 |
OMAi | SIMQQCN |
OrthoDBi | EOG091G065P |
PhylomeDBi | Q9JI11 |
TreeFami | TF354217 |
Family and domain databases
InterProi | View protein in InterPro IPR011009 Kinase-like_dom_sf IPR024205 Mst1_SARAH_domain IPR000719 Prot_kinase_dom IPR017441 Protein_kinase_ATP_BS IPR011524 SARAH_dom |
Pfami | View protein in Pfam PF11629 Mst1_SARAH, 1 hit PF00069 Pkinase, 1 hit |
SMARTi | View protein in SMART SM00220 S_TKc, 1 hit |
SUPFAMi | SSF56112 SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS00107 PROTEIN_KINASE_ATP, 1 hit PS50011 PROTEIN_KINASE_DOM, 1 hit PS50951 SARAH, 1 hit |
i Sequence
Sequence statusi: Complete.
: The displayed sequence is further processed into a mature form. Sequence processingi
Q9JI11-1 [UniParc]FASTAAdd to basket
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
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 |
CCDSi | CCDS17021.1 |
RefSeqi | NP_067395.1, NM_021420.3 |
UniGenei | Mm.234472 |
Genome annotation databases
Ensembli | ENSMUST00000018353; ENSMUSP00000018353; ENSMUSG00000018209 |
GeneIDi | 58231 |
KEGGi | mmu:58231 |
UCSCi | uc008ntt.1 mouse |
Similar proteinsi
Entry informationi
Entry namei | STK4_MOUSE | |
Accessioni | Q9JI11Primary (citable) accession number: Q9JI11 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | July 25, 2006 |
Last sequence update: | October 1, 2000 | |
Last modified: | April 25, 2018 | |
This is version 154 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |