SIAH2_MOUSE
ID SIAH2_MOUSE Reviewed; 325 AA.
AC Q06986;
DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT 26-APR-2004, sequence version 2.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=E3 ubiquitin-protein ligase SIAH2;
DE EC=2.3.2.27 {ECO:0000269|PubMed:26070566};
DE AltName: Full=RING-type E3 ubiquitin transferase SIAH2 {ECO:0000305};
DE AltName: Full=Seven in absentia homolog 2;
DE Short=Siah-2;
DE Short=mSiah2;
GN Name=Siah2;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=SWR/J;
RX PubMed=8404535; DOI=10.1242/dev.117.4.1333;
RA Della N.G., Senior P.V., Bowtell D.D.L.;
RT "Isolation and characterisation of murine homologues of the Drosophila
RT seven in absentia gene (sina).";
RL Development 117:1333-1343(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP TISSUE SPECIFICITY.
RX PubMed=7895278; DOI=10.1007/bf00318499;
RA Della N.G., Bowtell D.D.L., Beck F.;
RT "Expression of Siah-2, a vertebrate homologue of Drosophila sina, in germ
RT cells of the mouse ovary and testis.";
RL Cell Tissue Res. 279:411-419(1995).
RN [4]
RP FUNCTION IN DEGRADATION OF NCOR1.
RX PubMed=9637679; DOI=10.1101/gad.12.12.1775;
RA Zhang J., Guenther M.G., Carthew R.W., Lazar M.A.;
RT "Proteasomal regulation of nuclear receptor corepressor-mediated
RT repression.";
RL Genes Dev. 12:1775-1780(1998).
RN [5]
RP INTERACTION WITH PEG3.
RX PubMed=10681424; DOI=10.1073/pnas.040378897;
RA Relaix F., Wei X., Li W., Pan J., Lin Y., Bowtell D.D., Sassoon D.A.,
RA Wu X.;
RT "Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in
RT p53-mediated apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:2105-2110(2000).
RN [6]
RP FUNCTION IN DEGRADATION OF BAG1.
RX PubMed=11257006; DOI=10.1242/jcs.114.7.1409;
RA Sourisseau T., Desbois C., Debure L., Bowtell D.D.L., Cato A.C.B.,
RA Schneikert J., Moyse E., Michel D.;
RT "Alteration of the stability of Bag-1 protein in the control of olfactory
RT neuronal apoptosis.";
RL J. Cell Sci. 114:1409-1416(2001).
RN [7]
RP INDUCTION.
RX PubMed=12417719; DOI=10.1128/mcb.22.23.8155-8164.2002;
RA Frew I.J., Dickins R.A., Cuddihy A.R., Del Rosario M., Reinhard C.,
RA O'Connell M.J., Bowtell D.D.L.;
RT "Normal p53 function in primary cells deficient for Siah genes.";
RL Mol. Cell. Biol. 22:8155-8164(2002).
RN [8]
RP FUNCTION.
RX PubMed=14645526; DOI=10.1128/mcb.23.24.9150-9161.2003;
RA Frew I.J., Hammond V.E., Dickins R.A., Quinn J.M.W., Walkley C.R.,
RA Sims N.A., Schnall R., Della N.G., Holloway A.J., Digby M.R., Janes P.W.,
RA Tarlinton D.M., Purton L.E., Gillespie M.T., Bowtell D.D.L.;
RT "Generation and analysis of Siah2 mutant mice.";
RL Mol. Cell. Biol. 23:9150-9161(2003).
RN [9]
RP FUNCTION IN DEGRADATION OF PML.
RX PubMed=14645235; DOI=10.1074/jbc.m306407200;
RA Fanelli M., Fantozzi A., De Luca P., Caprodossi S., Matsuzawa S.,
RA Lazar M.A., Pelicci P.G., Minucci S.;
RT "The coiled-coil domain is the structural determinant for mammalian
RT homologues of Drosophila Sina-mediated degradation of promyelocytic
RT leukemia protein and other tripartite motif proteins by the proteasome.";
RL J. Biol. Chem. 279:5374-5379(2004).
RN [10]
RP PHOSPHORYLATION AT THR-24 AND SER-29, AND FUNCTION.
RX PubMed=17003045; DOI=10.1074/jbc.m606568200;
RA Khurana A., Nakayama K., Williams S., Davis R.J., Mustelin T., Ronai Z.;
RT "Regulation of the ring finger E3 ligase Siah2 by p38 MAPK.";
RL J. Biol. Chem. 281:35316-35326(2006).
RN [11]
RP FUNCTION, AND INDUCTION.
RX PubMed=24809345; DOI=10.1371/journal.pgen.1004348;
RA Scortegagna M., Kim H., Li J.L., Yao H., Brill L.M., Han J., Lau E.,
RA Bowtell D., Haddad G., Kaufman R.J., Ronai Z.A.;
RT "Fine tuning of the UPR by the ubiquitin ligases Siah1/2.";
RL PLoS Genet. 10:e1004348-e1004348(2014).
RN [12]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=26070566; DOI=10.1074/jbc.m115.637660;
RA Huang J., Cardamone M.D., Johnson H.E., Neault M., Chan M., Floyd Z.E.,
RA Mallette F.A., Perissi V.;
RT "Exchange factor TBL1 and arginine methyltransferase PRMT6 cooperate in
RT protecting G protein pathway suppressor 2 (GPS2) from proteasomal
RT degradation.";
RL J. Biol. Chem. 290:19044-19054(2015).
RN [13]
RP FUNCTION.
RX PubMed=26392558; DOI=10.1073/pnas.1501204112;
RA DeBruyne J.P., Baggs J.E., Sato T.K., Hogenesch J.B.;
RT "Ubiquitin ligase Siah2 regulates RevErbalpha degradation and the mammalian
RT circadian clock.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:12420-12425(2015).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination and
CC subsequent proteasomal degradation of target proteins (PubMed:11257006,
CC PubMed:14645235, PubMed:14645526, PubMed:17003045, PubMed:9637679,
CC PubMed:24809345, PubMed:26070566). E3 ubiquitin ligases accept
CC ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a
CC thioester and then directly transfers the ubiquitin to targeted
CC substrates (PubMed:11257006, PubMed:14645235, PubMed:14645526,
CC PubMed:17003045, PubMed:9637679, PubMed:26070566). Mediates E3
CC ubiquitin ligase activity either through direct binding to substrates
CC or by functioning as the essential RING domain subunit of larger E3
CC complexes (PubMed:11257006, PubMed:14645235, PubMed:14645526,
CC PubMed:17003045, PubMed:9637679, PubMed:26070566). Mediates
CC ubiquitination and proteasomal degradation of DYRK2 in response to
CC hypoxia. Promotes monoubiquitination of SNCA (By similarity). Triggers
CC the ubiquitin-mediated degradation of many substrates, including
CC proteins involved in transcription regulation (GPS2, POU2AF1, PML,
CC NCOR1), a cell surface receptor (DCC), an antiapoptotic protein (BAG1),
CC and a protein involved in synaptic vesicle function in neurons (SYP)
CC (PubMed:11257006, PubMed:14645235, PubMed:14645526, PubMed:17003045,
CC PubMed:9637679, PubMed:26070566). It is thereby involved in apoptosis,
CC tumor suppression, cell cycle, transcription and signaling processes
CC (PubMed:11257006, PubMed:14645235, PubMed:14645526, PubMed:17003045,
CC PubMed:9637679, PubMed:26070566). Has some overlapping function with
CC SIAH1. Triggers the ubiquitin-mediated degradation of TRAF2, whereas
CC SIAH1 does not. Regulates cellular clock function via ubiquitination of
CC the circadian transcriptional repressors NR1D1 and NR1D2 leading to
CC their proteasomal degradation (By similarity). Plays an important role
CC in mediating the rhythmic degradation/clearance of NR1D1 and NR1D2
CC contributing to their circadian profile of protein abundance
CC (PubMed:26392558). Mediates ubiquitination and degradation of EGLN2 and
CC EGLN3 in response to the unfolded protein response (UPR), leading to
CC their degradation and subsequent stabilization of ATF4
CC (PubMed:24809345). Also part of the Wnt signaling pathway in which it
CC mediates the Wnt-induced ubiquitin-mediated proteasomal degradation of
CC AXIN1 (By similarity). {ECO:0000250|UniProtKB:O43255,
CC ECO:0000269|PubMed:11257006, ECO:0000269|PubMed:14645235,
CC ECO:0000269|PubMed:14645526, ECO:0000269|PubMed:17003045,
CC ECO:0000269|PubMed:24809345, ECO:0000269|PubMed:26070566,
CC ECO:0000269|PubMed:26392558, ECO:0000269|PubMed:9637679}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:26070566};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Homodimer (By similarity). Interacts with UBE2E2 (By
CC similarity). Interacts with VAV1, without mediating its ubiquitin-
CC mediated degradation (By similarity). Interacts with CACYBP/SIP (By
CC similarity). Probable component of some large E3 complex possibly
CC composed of UBE2D1, SIAH2, CACYBP/SIP, SKP1, APC and TBL1X (By
CC similarity). Interacts with UBE2I (By similarity). Interacts with
CC PEG10, which may inhibit its activity (By similarity). Interacts with
CC EGLN2 and SNCAIP (By similarity). Interacts with DYRK2 (By similarity).
CC Interacts with PEG3 (PubMed:10681424). Interacts with NR1D1 and NR1D2
CC (By similarity). Interacts with DCC (By similarity). Interacts with
CC AXIN1. {ECO:0000250|UniProtKB:O43255, ECO:0000269|PubMed:10681424}.
CC -!- INTERACTION:
CC Q06986; O08715: Akap1; NbExp=6; IntAct=EBI-957413, EBI-7838029;
CC Q06986; P10275: AR; Xeno; NbExp=6; IntAct=EBI-957413, EBI-608057;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:O43255}. Nucleus
CC {ECO:0000250|UniProtKB:O43255}. Note=Predominantly cytoplasmic.
CC Partially nuclear. {ECO:0000250|UniProtKB:O43255}.
CC -!- TISSUE SPECIFICITY: Widely expressed at low level in embryos and
CC adults. Expressed in a specific population of germ cells within both
CC the mouse ovary and testis. Absent in primordial oocytes but expressed
CC in all growing oocytes, coincident with their recruitment from the pool
CC of quiescent cells. Its level of expression increases as the oocytes
CC mature. Expressed in Graafian follicles and in fertilized zygotes up
CC until the two cell stage, a time of extensive maternal transcript
CC degradation and zygotic gene activation. Expressed in the testis from
CC postmeiotic spermatids. {ECO:0000269|PubMed:7895278,
CC ECO:0000269|PubMed:8404535}.
CC -!- INDUCTION: May be induced by p53/TP53, suggesting that it may be
CC required to modulate p53/TP53 response (PubMed:12417719). The relevance
CC of such activity in vivo is however unclear and may not exist
CC (PubMed:12417719). Induced by ATF4 in response to the unfolded protein
CC response (UPR) (PubMed:24809345). {ECO:0000269|PubMed:12417719,
CC ECO:0000269|PubMed:24809345}.
CC -!- DOMAIN: The RING-type zinc finger domain is essential for ubiquitin
CC ligase activity.
CC -!- DOMAIN: The SBD domain (substrate-binding domain) mediates the
CC homodimerization and the interaction with substrate proteins. It is
CC related to the TRAF family. {ECO:0000250|UniProtKB:P61092}.
CC -!- PTM: Phosphorylated at Ser-29 by DYRK2; this increases the ubiquitin
CC ligase activity and promotes degradation of EGLN3 (By similarity).
CC Phosphorylated at Thr-24 and Ser-29 by MAPK14, which mediates the
CC degradation by the proteasome of EGLN3. {ECO:0000250|UniProtKB:O43255,
CC ECO:0000269|PubMed:17003045}.
CC -!- SIMILARITY: Belongs to the SINA (Seven in absentia) family.
CC {ECO:0000305}.
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DR EMBL; Z19581; CAA79632.1; -; mRNA.
DR EMBL; BC058400; AAH58400.1; -; mRNA.
DR CCDS; CCDS17368.1; -.
DR PIR; I48765; I48765.
DR RefSeq; NP_033200.2; NM_009174.3.
DR AlphaFoldDB; Q06986; -.
DR SMR; Q06986; -.
DR BioGRID; 203233; 9.
DR IntAct; Q06986; 5.
DR MINT; Q06986; -.
DR STRING; 10090.ENSMUSP00000067496; -.
DR iPTMnet; Q06986; -.
DR PhosphoSitePlus; Q06986; -.
DR PaxDb; Q06986; -.
DR PeptideAtlas; Q06986; -.
DR PRIDE; Q06986; -.
DR ProteomicsDB; 261037; -.
DR Antibodypedia; 33601; 245 antibodies from 29 providers.
DR DNASU; 20439; -.
DR Ensembl; ENSMUST00000070368; ENSMUSP00000067496; ENSMUSG00000036432.
DR GeneID; 20439; -.
DR KEGG; mmu:20439; -.
DR UCSC; uc008pia.1; mouse.
DR CTD; 6478; -.
DR MGI; MGI:108062; Siah2.
DR VEuPathDB; HostDB:ENSMUSG00000036432; -.
DR eggNOG; KOG3002; Eukaryota.
DR GeneTree; ENSGT00940000159812; -.
DR HOGENOM; CLU_028215_0_0_1; -.
DR InParanoid; Q06986; -.
DR OMA; NKPCGKQ; -.
DR OrthoDB; 780610at2759; -.
DR PhylomeDB; Q06986; -.
DR TreeFam; TF312976; -.
DR Reactome; R-MMU-373752; Netrin-1 signaling.
DR Reactome; R-MMU-5689880; Ub-specific processing proteases.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 20439; 2 hits in 73 CRISPR screens.
DR ChiTaRS; Siah2; mouse.
DR PRO; PR:Q06986; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; Q06986; protein.
DR Bgee; ENSMUSG00000036432; Expressed in secondary oocyte and 244 other tissues.
DR ExpressionAtlas; Q06986; baseline and differential.
DR Genevisible; Q06986; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005769; C:early endosome; ISO:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0043005; C:neuron projection; ISO:MGI.
DR GO; GO:0043025; C:neuronal cell body; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; ISO:MGI.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IMP:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; ISO:MGI.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:MGI.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISO:MGI.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:MGI.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; ISO:MGI.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0030163; P:protein catabolic process; ISO:MGI.
DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB.
DR GO; GO:0031396; P:regulation of protein ubiquitination; ISO:MGI.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR Gene3D; 2.60.210.10; -; 1.
DR Gene3D; 3.30.40.10; -; 2.
DR InterPro; IPR018121; 7-in-absentia-prot_TRAF-dom.
DR InterPro; IPR004162; SINA-like_animal.
DR InterPro; IPR008974; TRAF-like.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR013010; Znf_SIAH.
DR PANTHER; PTHR45877; PTHR45877; 1.
DR Pfam; PF03145; Sina; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
DR PROSITE; PS51081; ZF_SIAH; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Biological rhythms; Cell cycle; Cytoplasm; Metal-binding;
KW Nucleus; Phosphoprotein; Reference proteome; Transferase;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..325
FT /note="E3 ubiquitin-protein ligase SIAH2"
FT /id="PRO_0000056169"
FT ZN_FING 81..116
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 134..194
FT /note="SIAH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00455"
FT REGION 1..43
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 131..323
FT /note="SBD"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT COMPBIAS 14..32
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 139
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 146
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 158
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 162
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 169
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 176
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 188
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 193
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT MOD_RES 6
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43255"
FT MOD_RES 16
FT /note="Phosphoserine; by DYRK2"
FT /evidence="ECO:0000250|UniProtKB:O43255"
FT MOD_RES 24
FT /note="Phosphothreonine; by MAPK14"
FT /evidence="ECO:0000269|PubMed:17003045"
FT MOD_RES 29
FT /note="Phosphoserine; by DYRK2 and MAPK14"
FT /evidence="ECO:0000269|PubMed:17003045"
FT MOD_RES 69
FT /note="Phosphoserine; by DYRK2"
FT /evidence="ECO:0000250|UniProtKB:O43255"
FT MOD_RES 120
FT /note="Phosphothreonine; by DYRK2"
FT /evidence="ECO:0000250|UniProtKB:O43255"
FT CONFLICT 203..204
FT /note="DI -> ET (in Ref. 1; CAA79632)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 325 AA; 34758 MW; 1CB73AD3B4C9982F CRC64;
MSRPSSTGPS ANKPCSKQPP PPQTPHAPSP AAPPAAATIS AAGPGSSAVP AAAAVISGPG
AGGGADPVSP QHHELTSLFE CPVCFDYVLP PILQCQAGHL VCNQCRQKLS CCPTCRGALT
PSIRNLAMEK VASAVLFPCK YATTGCSLTL HHTEKPEHED ICEYRPYSCP CPGASCKWQG
SLEAVMSHLM HAHKSITTLQ GEDIVFLATD INLPGAVDWV MMQSCFGHHF MLVLEKQEKY
EGHQQFFAIV LLIGTRKQAE NFAYRLELNG NRRRLTWEAT PRSIHDGVAA AIMNSDCLVF
DTAIAHLFAD NGNLGINVTI STCCQ
