STK3_RAT
ID STK3_RAT Reviewed; 491 AA.
AC O54748;
DT 25-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Serine/threonine-protein kinase 3;
DE EC=2.7.11.1;
DE AltName: Full=Mammalian STE20-like protein kinase 2;
DE Short=MST-2;
DE AltName: Full=STE20-like kinase MST2;
DE Contains:
DE RecName: Full=Serine/threonine-protein kinase 3 36kDa subunit;
DE Short=MST2/N;
DE Contains:
DE RecName: Full=Serine/threonine-protein kinase 3 20kDa subunit;
DE Short=MST2/C;
GN Name=Stk3; Synonyms=Mst2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC TISSUE=Thyroid;
RX PubMed=9430685; DOI=10.1074/jbc.273.3.1477;
RA Aurisicchio L., Dilauro R., Zannini M.;
RT "Identification of the thyroid transcription factor 1 as a target for rat
RT MST2 kinase.";
RL J. Biol. Chem. 273:1477-1482(1998).
RN [2]
RP ACTIVITY REGULATION, AND PHOSPHORYLATION AT THR-180.
RX PubMed=12554736; DOI=10.1074/jbc.m211085200;
RA Deng Y., Pang A., Wang J.H.;
RT "Regulation of mammalian STE20-like kinase 2 (MST2) by protein
RT phosphorylation/dephosphorylation and proteolysis.";
RL J. Biol. Chem. 278:11760-11767(2003).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-316, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
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 (By similarity).
CC Phosphorylates NKX2-1. Phosphorylates NEK2 and plays a role in
CC centrosome disjunction by regulating the localization of NEK2 to
CC centrosomes, and its ability to phosphorylate CROCC and CEP250. In
CC conjunction with SAV1, activates the transcriptional activity of ESR1
CC through the modulation of its phosphorylation. Positively regulates
CC RAF1 activation via suppression of the inhibitory phosphorylation of
CC RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates
CC MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38
CC (By similarity). {ECO:0000250|UniProtKB:Q13188,
CC ECO:0000250|UniProtKB:Q9JI10, ECO:0000269|PubMed:9430685}.
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-180, which are
CC inhibited by the proto-oncogene product RAF1. Activated by RASSF1 which
CC 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 RAF1, which prevents dimerization and
CC phosphorylation. Interacts with RASSF1. Interacts (via SARAH domain)
CC with NEK2. Interacts with ESR1 only in the presence of SAV1. Interacts
CC with PKB/AKT1. Forms a tripartite complex with MOBKL1B and STK38.
CC Interacts with RASSF2 (via SARAH domain). Interacts with DLG5 (via PDZ
CC domain 3). Interacts with LATS1; this interaction is inhibited in the
CC presence of DLG5. Interacts with MARK3 in the presence of DLG5.
CC {ECO:0000250|UniProtKB:Q13188}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q13188}. Nucleus
CC {ECO:0000250|UniProtKB:Q13188}. Note=The caspase-cleaved form cycles
CC between nucleus and cytoplasm (By similarity). Phosphorylation at Thr-
CC 117 leads to inhibition of nuclear translocation (By similarity).
CC {ECO:0000250|UniProtKB:Q13188}.
CC -!- PTM: Phosphorylation at Thr-117 and Thr-384 by PKB/AKT1, leads to
CC inhibition of its: cleavage, kinase activity, autophosphorylation at
CC Thr-180, binding to RASSF1 and nuclear translocation, and increase in
CC its binding to RAF1. {ECO:0000250}.
CC -!- PTM: Proteolytically cleaved by caspase-3 during apoptosis. Proteolytic
CC cleavage results in kinase activation and nuclear translocation of the
CC truncated form (MST1/N) (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; AJ001529; CAA04814.1; -; mRNA.
DR RefSeq; NP_113923.1; NM_031735.1.
DR AlphaFoldDB; O54748; -.
DR SMR; O54748; -.
DR IntAct; O54748; 1.
DR MINT; O54748; -.
DR STRING; 10116.ENSRNOP00000062778; -.
DR iPTMnet; O54748; -.
DR PhosphoSitePlus; O54748; -.
DR PaxDb; O54748; -.
DR PRIDE; O54748; -.
DR GeneID; 65189; -.
DR KEGG; rno:65189; -.
DR UCSC; RGD:68412; rat.
DR CTD; 6788; -.
DR RGD; 68412; Stk3.
DR eggNOG; KOG0574; Eukaryota.
DR InParanoid; O54748; -.
DR OrthoDB; 967913at2759; -.
DR PhylomeDB; O54748; -.
DR PRO; PR:O54748; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISO:RGD.
DR GO; GO:0005524; F:ATP binding; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0000287; F:magnesium ion binding; ISO:RGD.
DR GO; GO:0004672; F:protein kinase activity; ISS:UniProtKB.
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:0060706; P:cell differentiation involved in embryonic placenta development; ISO:RGD.
DR GO; GO:0007417; P:central nervous system development; ISO:RGD.
DR GO; GO:0003157; P:endocardium development; ISO:RGD.
DR GO; GO:0097284; P:hepatocyte apoptotic process; ISO:RGD.
DR GO; GO:0035329; P:hippo signaling; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; ISO:RGD.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISO:RGD.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:RGD.
DR GO; GO:0046621; P:negative regulation of organ growth; ISO:RGD.
DR GO; GO:0001841; P:neural tube formation; ISO:RGD.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:RGD.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; ISO:RGD.
DR GO; GO:1902043; P:positive regulation of extrinsic apoptotic signaling pathway via death domain receptors; ISO:RGD.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; ISO:RGD.
DR GO; GO:0046330; P:positive regulation of JNK cascade; ISO:RGD.
DR GO; GO:0032092; P:positive regulation of protein binding; ISO:RGD.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISO:RGD.
DR GO; GO:0060215; P:primitive hemopoiesis; ISO:RGD.
DR GO; GO:0006606; P:protein import into nucleus; ISO:RGD.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; ISO:RGD.
DR GO; GO:0051262; P:protein tetramerization; IEA:InterPro.
DR GO; GO:0060800; P:regulation of cell differentiation involved in embryonic placenta development; ISO:RGD.
DR GO; GO:0043408; P:regulation of MAPK cascade; IBA:GO_Central.
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 1: Evidence at protein level;
KW Acetylation; Apoptosis; ATP-binding; Coiled coil; Cytoplasm; Kinase;
KW Magnesium; Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..491
FT /note="Serine/threonine-protein kinase 3"
FT /id="PRO_0000247764"
FT CHAIN 1..322
FT /note="Serine/threonine-protein kinase 3 36kDa subunit"
FT /id="PRO_0000413717"
FT CHAIN 323..491
FT /note="Serine/threonine-protein kinase 3 20kDa subunit"
FT /id="PRO_0000413718"
FT DOMAIN 27..278
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 437..484
FT /note="SARAH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00310"
FT REGION 301..343
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 370..392
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 291..324
FT /evidence="ECO:0000255"
FT COMPBIAS 327..343
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 146
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 33..41
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 56
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 322..323
FT /note="Cleavage; by caspase-3"
FT /evidence="ECO:0000250"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q13188"
FT MOD_RES 15
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13188"
FT MOD_RES 117
FT /note="Phosphothreonine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:Q13188"
FT MOD_RES 180
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:12554736"
FT MOD_RES 316
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 336
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q13188"
FT MOD_RES 384
FT /note="Phosphothreonine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:Q13188"
FT MOD_RES 385
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13188"
FT MOD_RES 444
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13188"
SQ SEQUENCE 491 AA; 56122 MW; 90FA6B020E7FFD62 CRC64;
MEQPPAPKSK LKKLSEDSLT KQPEEVFDVL EKLGEGSYGS VFKAIHKESG QVVAIKQVPV
ESDVQEIIKE ISIMQQCDSP YVVKYYGSYF KNTDLWIVME YCGAGSVSDI IRLRNKTLTE
DEIATILKST LKGLEYLHFM RKIHRDIKAG NILLNTEGHA KLADFGVAGQ LTDTMAKRNT
VIGTPFWMAP EVIQEIGYNC VADIWSLGIT SIEMAEGKPP YADIHPMRAI FMIPTNPPPT
FRKPELWSDD FTDFVKKCLV KSPEQRATAT QLLQHPFIKN AKPVSILREL ITEGMEIKAK
RHEEQQRELE DEEENSDEDE LDSHTMVKTS SEGVGTMRAT STMSEGAQTM IEHNSTMLES
DLGTMVINSE DEEEEDGTMK RNATSPQVQR PSFMDYFDKQ DFKNKSHENC DQSMREPCPM
SNNVFPDNWR VPQDGDFDFL KNLSLEELQM RLKALDPMME REIEELHQRY SAKRQPILDA
MDAKKRRQQN F
