STK4_CHLAE
ID STK4_CHLAE Reviewed; 487 AA.
AC A4K2Y1;
DT 29-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2007, sequence version 1.
DT 03-AUG-2022, entry version 68.
DE RecName: Full=Serine/threonine-protein kinase 4;
DE EC=2.7.11.1;
DE Contains:
DE RecName: Full=Serine/threonine-protein kinase 4 37kDa subunit;
DE Short=MST1/N;
DE Contains:
DE RecName: Full=Serine/threonine-protein kinase 4 18kDa subunit;
DE Short=MST1/C;
GN Name=STK4;
OS Chlorocebus aethiops (Green monkey) (Cercopithecus aethiops).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Chlorocebus.
OX NCBI_TaxID=9534;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=17267810; DOI=10.1101/gr.6004607;
RG NISC comparative sequencing program;
RA Hurle B., Swanson W., Green E.D.;
RT "Comparative sequence analyses reveal rapid and divergent evolutionary
RT changes of the WFDC locus in the primate lineage.";
RL Genome Res. 17:276-286(2007).
CC -!- FUNCTION: Stress-activated, pro-apoptotic kinase which, following
CC caspase-cleavage, enters the nucleus and induces chromatin condensation
CC followed by internucleosomal DNA fragmentation. Key component of the
CC Hippo signaling pathway which plays a pivotal role in organ size
CC control and tumor suppression by restricting proliferation and
CC promoting apoptosis. The core of this pathway is composed of a kinase
CC cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory
CC protein SAV1, phosphorylates and activates LATS1/2 in complex with its
CC regulatory protein MOB1, which in turn phosphorylates and inactivates
CC YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2
CC inhibits its translocation into the nucleus to regulate cellular genes
CC important for cell proliferation, cell death, and cell migration.
CC STK3/MST2 and STK4/MST1 are required to repress proliferation of mature
CC hepatocytes, to prevent activation of facultative adult liver stem
CC cells (oval cells), and to inhibit tumor formation. Phosphorylates
CC 'Ser-14' of histone H2B (H2BS14ph) during apoptosis. Phosphorylates
CC FOXO3 upon oxidative stress, which results in its nuclear translocation
CC and cell death initiation. Phosphorylates MOBKL1A, MOBKL1B and RASSF2.
CC Phosphorylates TNNI3 (cardiac Tn-I) and alters its binding affinity to
CC TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Phosphorylates FOXO1 on
CC 'Ser-212' and regulates its activation and stimulates transcription of
CC PMAIP1 in a FOXO1-dependent manner. Phosphorylates SIRT1 and inhibits
CC SIRT1-mediated p53/TP53 deacetylation, thereby promoting p53/TP53
CC dependent transcription and apoptosis upon DNA damage. Acts as an
CC inhibitor of PKB/AKT1. Phosphorylates AR on 'Ser-650' and suppresses
CC its activity by intersecting with PKB/AKT1 signaling and antagonizing
CC formation of AR-chromatin complexes. {ECO:0000250|UniProtKB:Q13043,
CC ECO:0000250|UniProtKB:Q9JI11}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC -!- ACTIVITY REGULATION: Inhibited by the C-terminal non-catalytic region.
CC Activated by caspase-cleavage. Full activation also requires
CC homodimerization and autophosphorylation of Thr-183. Activated by
CC RASSF1 which acts by preventing its dephosphorylation (By similarity).
CC {ECO:0000250}.
CC -!- SUBUNIT: Homodimer; mediated via the coiled-coil region. Interacts with
CC NORE1, which inhibits autoactivation. Interacts with and stabilizes
CC SAV1. Interacts with RASSF1. Interacts with FOXO3. Interacts with
CC RASSF2 (via SARAH domain). Interacts with AR, PKB/AKT1, TNNI3 and
CC SIRT1. Interacts with DLG5 (via PDZ domain 3). Interacts with MARK3 and
CC SCRIB in the presence of DLG5. {ECO:0000250|UniProtKB:Q13043}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}.
CC Note=The caspase-cleaved form cycles between the nucleus and cytoplasm.
CC {ECO:0000250}.
CC -!- PTM: Autophosphorylated on serine and threonine residues.
CC Phosphorylation at Thr-387 by PKB/AKT1, leads to inhibition of its:
CC kinase activity, nuclear translocation and autophosphorylation at Thr-
CC 183. It also diminishes its cleavage by caspases and its ability to
CC phosphorylate FOXO3 (By similarity). {ECO:0000250|UniProtKB:Q13043}.
CC -!- PTM: Proteolytically cleaved by caspase-3 during apoptosis at Asp-326
CC and Asp-349 resulting in a 37 kDa or a 39 kDa subunit respectively. The
CC 39 kDa subunit is further cleaved into the 37 kDa form. Proteolytic
CC cleavage results in kinase activation and nuclear translocation of the
CC truncated form (MST1/N). It is less likely that cleavage at Asp-349 is
CC a prerequisite for activation as this site is not conserved in the
CC murine ortholog (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. STE20 subfamily. {ECO:0000305}.
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DR EMBL; DP000048; ABO53016.1; -; Genomic_DNA.
DR AlphaFoldDB; A4K2Y1; -.
DR SMR; A4K2Y1; -.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0035329; P:hippo signaling; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR GO; GO:0051262; P:protein tetramerization; IEA:InterPro.
DR Gene3D; 4.10.170.10; -; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR024205; Mst1_SARAH_domain.
DR InterPro; IPR036674; p53_tetramer_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR011524; SARAH_dom.
DR Pfam; PF11629; Mst1_SARAH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS50951; SARAH; 1.
PE 3: Inferred from homology;
KW Acetylation; Apoptosis; ATP-binding; Coiled coil; Cytoplasm; Kinase;
KW Magnesium; Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..487
FT /note="Serine/threonine-protein kinase 4"
FT /id="PRO_0000289628"
FT CHAIN 1..326
FT /note="Serine/threonine-protein kinase 4 37kDa subunit"
FT /evidence="ECO:0000250"
FT /id="PRO_0000413731"
FT CHAIN 327..487
FT /note="Serine/threonine-protein kinase 4 18kDa subunit"
FT /evidence="ECO:0000250"
FT /id="PRO_0000413732"
FT DOMAIN 30..281
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 433..480
FT /note="SARAH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00310"
FT REGION 303..332
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 290..310
FT /evidence="ECO:0000255"
FT ACT_SITE 149
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 36..44
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 59
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 326..327
FT /note="Cleavage; by caspase-3"
FT /evidence="ECO:0000250"
FT SITE 349..350
FT /note="Cleavage; by caspase-3"
FT /evidence="ECO:0000250"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q13043"
FT MOD_RES 3
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13043"
FT MOD_RES 183
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q13043"
FT MOD_RES 265
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13043"
FT MOD_RES 320
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13043"
FT MOD_RES 340
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13043"
FT MOD_RES 367
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13043"
FT MOD_RES 387
FT /note="Phosphothreonine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:Q13043"
FT MOD_RES 410
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13043"
FT MOD_RES 414
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13043"
FT MOD_RES 433
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9JI11"
SQ SEQUENCE 487 AA; 55632 MW; DBF0E52A8DFD189C CRC64;
METVQLRNPP RRQLKKLDED SLTKQPEEVF DVLEKLGEGS YGSVYKAIHK ETGQIVAIKQ
VPVESDLQEI IKEISIMQQC DSPHVVKYYG SYFKNTDLWI VMEYCGAGSV SDIIRLRNKT
LTEDEIATIL QSTLKGLEYL HFMRKIHRDI KAGNILLNTE GHAKLADFGV AGQLTDTMAK
RNTVIGTPFW MAPEVIQEIG YNCVADIWSL GITAIEMAEG KPPYADIHPM RAIFMIPTNP
PPTFRKPELW SDNFTDFVKQ CLVKSPEQRA TATQLLQHPF VKSAKGVSIL RDLINEAMDV
KLKRQESQQR EVDQDDEENS EEDEMDSGTM VRAVGDEMGT VRVASTMTDG ANTMIEHDDT
LPSQLGTMVI NTEDEEEEGT MKRRDETMQP AKPSFLEYFE QKEKENQINS FGKSVPGPLK
NSSDWKIPQD GDYEFLKSWT VEDLQKRLLA LDPMMEQEIE EIRQKYQSKR QPILDAIEAK
KRRQQNF
