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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
 
 
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