HGS_RAT
ID HGS_RAT Reviewed; 776 AA.
AC Q9JJ50; P97847; Q5XIV8; Q76N76;
DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 155.
DE RecName: Full=Hepatocyte growth factor-regulated tyrosine kinase substrate;
DE AltName: Full=SNAP-25-interacting protein Hrs-2;
GN Name=Hgs; Synonyms=Hrs, Hrs2;
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] (ISOFORM 1), TISSUE SPECIFICITY, AND INTERACTION
RP WITH SNAP25.
RX PubMed=9039916; DOI=10.1038/385826a0;
RA Bean A.J., Seifert R., Chen Y.A., Sacks R., Scheller R.H.;
RT "Hrs-2 is an ATPase implicated in calcium-regulated secretion.";
RL Nature 385:826-829(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
RC STRAIN=Wistar; TISSUE=Brain;
RX PubMed=9798906; DOI=10.1046/j.1471-4159.1998.71051827.x;
RA Ogura K., Kohno K., Tai T.;
RT "Molecular cloning of a rat brain cDNA, with homology to a tyrosine kinase
RT substrate, that induces galactosylceramide expression in COS-7 cells.";
RL J. Neurochem. 71:1827-1836(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, SUBCELLULAR
RP LOCATION, DOMAIN, AND INTERACTION WITH SNAP25.
RX PubMed=10825299; DOI=10.1242/jcs.113.12.2273;
RA Kwong J., Roudabush F.L., Moore P.H., Montague M., Oldham W., Li Y.,
RA Chin L.-S., Li L.;
RT "Hrs interacts with SNAP-25 and regulates Ca2+-dependent exocytosis.";
RL J. Cell Sci. 113:2273-2284(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
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 [5]
RP INTERACTION WITH EPS15.
RX PubMed=10809762; DOI=10.1074/jbc.275.20.15271;
RA Bean A.J., Davanger S., Chou M.F., Gerhardt B., Tsujimoto S., Chang Y.;
RT "Hrs-2 regulates receptor-mediated endocytosis via interactions with
RT Eps15.";
RL J. Biol. Chem. 275:15271-15278(2000).
RN [6]
RP INTERACTION WITH SNX1, AND DOMAIN.
RX PubMed=11110793; DOI=10.1074/jbc.m004129200;
RA Chin L.-S., Raynor M.C., Wei X., Chen H.-Q., Li L.;
RT "Hrs interacts with sorting nexin 1 and regulates degradation of epidermal
RT growth factor receptor.";
RL J. Biol. Chem. 276:7069-7078(2001).
RN [7]
RP INTERACTION WITH TRAK2.
RX PubMed=17062640; DOI=10.1242/jcs.03249;
RA Kirk E., Chin L.S., Li L.;
RT "GRIF1 binds Hrs and is a new regulator of endosomal trafficking.";
RL J. Cell Sci. 119:4689-4701(2006).
CC -!- FUNCTION: Involved in intracellular signal transduction mediated by
CC cytokines and growth factors. When associated with STAM, it suppresses
CC DNA signaling upon stimulation by IL-2 and GM-CSF. Could be a direct
CC effector of PI3-kinase in vesicular pathway via early endosomes and may
CC regulate trafficking to early and late endosomes by recruiting
CC clathrin. May concentrate ubiquitinated receptors within clathrin-
CC coated regions. Involved in down-regulation of receptor tyrosine kinase
CC via multivesicular body (MVBs) when complexed with STAM (ESCRT-0
CC complex). The ESCRT-0 complex binds ubiquitin and acts as sorting
CC machinery that recognizes ubiquitinated receptors and transfers them to
CC further sequential lysosomal sorting/trafficking processes. Involved in
CC receptor recycling via its association with the CART complex, a
CC multiprotein complex required for efficient transferrin receptor
CC recycling but not for EGFR degradation (By similarity). May contribute
CC to the efficient recruitment of SMADs to the activin receptor complex.
CC {ECO:0000250}.
CC -!- SUBUNIT: Component of the ESCRT-0 complex composed of STAM or STAM2 and
CC HGS. Part of a complex at least composed of HSG, STAM2 (or probably
CC STAM) and EPS15 (By similarity). Interacts with STAM (By similarity).
CC Interacts with STAM2 (By similarity). Interacts with EPS15; the
CC interaction is direct, calcium-dependent and inhibited by SNAP25
CC (PubMed:10809762). Identified in a complex with STAM and LITAF (By
CC similarity). Found in a complex with STAM and E3 ligase ITCH and DTX3L
CC (By similarity). Interacts with E3 ligase DTX3L; the interaction brings
CC together STAM and HSG, promotes their recruitment to early endosomes
CC and decreases STAM and HGS ubiquitination by ITCH (By similarity).
CC Interacts with NF2; the interaction is direct (By similarity).
CC Interacts with ubiquitin; the interaction is direct (By similarity).
CC Interacts with VPS37C (By similarity). Interacts with SMAD1, SMAD2 and
CC SMAD3 (By similarity). Interacts with TSG101; the interaction mediates
CC the association with the ESCRT-I complex (By similarity). Interacts
CC with SNAP25; the interaction is direct and decreases with addition of
CC increasing concentrations of free calcium (PubMed:9039916,
CC PubMed:10825299). Interacts with SNX1; the interaction is direct
CC (PubMed:11110793). Component of a 550 kDa membrane complex at least
CC composed of HGS and SNX1 but excluding EGFR (PubMed:11110793).
CC Interacts with TRAK2 (PubMed:17062640). Interacts with TRAK1 (By
CC similarity). Component of the CART complex, at least composed of ACTN4,
CC HGS/HRS, MYO5B and TRIM3 (By similarity). Interacts (via UIM domain)
CC with UBQLN1 (via ubiquitin-like domain) (By similarity). Interacts with
CC ARRDC3 (By similarity). Identified in a complex containing at least
CC ARRDC4, AVPR2 and HGS (By similarity). Interacts with LAPTM4B; promotes
CC HGS ubiquitination (By similarity). {ECO:0000250|UniProtKB:O14964,
CC ECO:0000250|UniProtKB:Q99LI8, ECO:0000269|PubMed:10809762,
CC ECO:0000269|PubMed:10825299, ECO:0000269|PubMed:11110793,
CC ECO:0000269|PubMed:17062640, ECO:0000269|PubMed:9039916}.
CC -!- INTERACTION:
CC Q9JJ50; P54256: Hap1; NbExp=5; IntAct=EBI-7092491, EBI-994539;
CC Q9JJ50; P54256-2: Hap1; NbExp=5; IntAct=EBI-7092491, EBI-994554;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:10825299}. Early
CC endosome membrane {ECO:0000269|PubMed:10825299}; Peripheral membrane
CC protein {ECO:0000269|PubMed:10825299}; Cytoplasmic side
CC {ECO:0000269|PubMed:10825299}. Endosome, multivesicular body membrane
CC {ECO:0000269|PubMed:10825299}; Peripheral membrane protein
CC {ECO:0000269|PubMed:10825299}. Note=Colocalizes with UBQLN1 in
CC ubiquitin-rich cytoplasmic aggregates that are not endocytic
CC compartments. {ECO:0000250|UniProtKB:O14964}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9JJ50-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9JJ50-2; Sequence=VSP_014852;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC {ECO:0000269|PubMed:10825299, ECO:0000269|PubMed:9039916,
CC ECO:0000269|PubMed:9798906}.
CC -!- DOMAIN: Has a double-sided UIM that can bind 2 ubiquitin molecules, one
CC on each side of the helix. {ECO:0000250}.
CC -!- DOMAIN: The FYVE-type zinc finger domain mediates interactions with
CC phosphatidylinositol 3-phosphate in membranes of early endosomes and
CC penetrates bilayers. The FYVE domain insertion into PtdIns(3)P-enriched
CC membranes is substantially increased in acidic conditions (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Phosphorylated on Tyr-334. This phosphorylation occurs in response
CC to EGF. A minor site of phosphorylation on Tyr-329 is detected. Protein
CC phosphorylation may also be triggered in response to IL-2, GM-CSF and
CC HGF (By similarity). {ECO:0000250|UniProtKB:Q99LI8}.
CC -!- PTM: Ubiquitinated by ITCH. {ECO:0000250|UniProtKB:O14964}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB49681.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; U87863; AAB49681.1; ALT_FRAME; mRNA.
DR EMBL; AB002811; BAD08342.1; -; mRNA.
DR EMBL; AF036344; AAF76251.1; -; mRNA.
DR EMBL; BC083561; AAH83561.1; -; mRNA.
DR RefSeq; NP_062260.2; NM_019387.2. [Q9JJ50-2]
DR AlphaFoldDB; Q9JJ50; -.
DR SMR; Q9JJ50; -.
DR BioGRID; 248562; 7.
DR CORUM; Q9JJ50; -.
DR IntAct; Q9JJ50; 1.
DR MINT; Q9JJ50; -.
DR CarbonylDB; Q9JJ50; -.
DR iPTMnet; Q9JJ50; -.
DR PhosphoSitePlus; Q9JJ50; -.
DR jPOST; Q9JJ50; -.
DR PaxDb; Q9JJ50; -.
DR PRIDE; Q9JJ50; -.
DR GeneID; 56084; -.
DR KEGG; rno:56084; -.
DR CTD; 9146; -.
DR RGD; 69225; Hgs.
DR eggNOG; KOG1818; Eukaryota.
DR HOGENOM; CLU_013062_1_0_1; -.
DR InParanoid; Q9JJ50; -.
DR OrthoDB; 828765at2759; -.
DR PhylomeDB; Q9JJ50; -.
DR Reactome; R-RNO-182971; EGFR downregulation.
DR Reactome; R-RNO-432720; Lysosome Vesicle Biogenesis.
DR Reactome; R-RNO-5689880; Ub-specific processing proteases.
DR Reactome; R-RNO-6807004; Negative regulation of MET activity.
DR Reactome; R-RNO-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-RNO-8856828; Clathrin-mediated endocytosis.
DR Reactome; R-RNO-9013420; RHOU GTPase cycle.
DR Reactome; R-RNO-917729; Endosomal Sorting Complex Required For Transport (ESCRT).
DR Reactome; R-RNO-9706019; RHOBTB3 ATPase cycle.
DR PRO; PR:Q9JJ50; -.
DR Proteomes; UP000002494; Unplaced.
DR Genevisible; Q9JJ50; RN.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0005769; C:early endosome; ISO:RGD.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0033565; C:ESCRT-0 complex; ISO:RGD.
DR GO; GO:0016020; C:membrane; IDA:RGD.
DR GO; GO:0032585; C:multivesicular body membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030141; C:secretory granule; IDA:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0035091; F:phosphatidylinositol binding; IEA:InterPro.
DR GO; GO:0019904; F:protein domain specific binding; ISO:RGD.
DR GO; GO:0043130; F:ubiquitin binding; IBA:GO_Central.
DR GO; GO:0140036; F:ubiquitin-dependent protein binding; ISO:RGD.
DR GO; GO:0044389; F:ubiquitin-like protein ligase binding; ISO:RGD.
DR GO; GO:0032456; P:endocytic recycling; IBA:GO_Central.
DR GO; GO:0008333; P:endosome to lysosome transport; IMP:RGD.
DR GO; GO:0010324; P:membrane invagination; ISO:RGD.
DR GO; GO:0016525; P:negative regulation of angiogenesis; ISO:RGD.
DR GO; GO:0010642; P:negative regulation of platelet-derived growth factor receptor signaling pathway; ISO:RGD.
DR GO; GO:0046426; P:negative regulation of receptor signaling pathway via JAK-STAT; ISO:RGD.
DR GO; GO:0030948; P:negative regulation of vascular endothelial growth factor receptor signaling pathway; ISO:RGD.
DR GO; GO:1903543; P:positive regulation of exosomal secretion; ISO:RGD.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR GO; GO:0072657; P:protein localization to membrane; ISO:RGD.
DR GO; GO:0006622; P:protein targeting to lysosome; ISO:RGD.
DR GO; GO:0031623; P:receptor internalization; IBA:GO_Central.
DR GO; GO:0043405; P:regulation of MAP kinase activity; ISO:RGD.
DR Gene3D; 1.25.40.90; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR008942; ENTH_VHS.
DR InterPro; IPR017073; HGS/VPS27.
DR InterPro; IPR024641; HRS_helical.
DR InterPro; IPR003903; UIM_dom.
DR InterPro; IPR002014; VHS_dom.
DR InterPro; IPR000306; Znf_FYVE.
DR InterPro; IPR017455; Znf_FYVE-rel.
DR InterPro; IPR011011; Znf_FYVE_PHD.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR PANTHER; PTHR46275; PTHR46275; 1.
DR Pfam; PF01363; FYVE; 1.
DR Pfam; PF12210; Hrs_helical; 1.
DR Pfam; PF00790; VHS; 1.
DR PIRSF; PIRSF036956; Hrs_Vps27; 1.
DR SMART; SM00064; FYVE; 1.
DR SMART; SM00288; VHS; 1.
DR SUPFAM; SSF48464; SSF48464; 1.
DR SUPFAM; SSF57903; SSF57903; 1.
DR PROSITE; PS50330; UIM; 1.
DR PROSITE; PS50179; VHS; 1.
DR PROSITE; PS50178; ZF_FYVE; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cytoplasm; Endosome; Membrane;
KW Metal-binding; Phosphoprotein; Protein transport; Reference proteome;
KW Transport; Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..776
FT /note="Hepatocyte growth factor-regulated tyrosine kinase
FT substrate"
FT /id="PRO_0000098710"
FT DOMAIN 15..143
FT /note="VHS"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00218"
FT DOMAIN 258..277
FT /note="UIM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00213"
FT ZN_FING 160..220
FT /note="FYVE-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT REGION 223..319
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 225..542
FT /note="Interaction with SNX1"
FT /evidence="ECO:0000269|PubMed:11110793"
FT REGION 338..401
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 444..542
FT /note="Interaction with SNAP25 and TRAK2"
FT /evidence="ECO:0000269|PubMed:17062640"
FT REGION 453..571
FT /note="Interaction with STAM"
FT /evidence="ECO:0000250|UniProtKB:Q99LI8"
FT REGION 479..776
FT /note="Interaction with NF2"
FT /evidence="ECO:0000250"
FT REGION 719..776
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 233..252
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 272..286
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 375..397
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 719..745
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 746..764
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 166
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 169
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 182
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 185
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 190
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 193
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 212
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT BINDING 215
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00091"
FT MOD_RES 207
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:O14964"
FT MOD_RES 216
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O14964"
FT MOD_RES 308
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q99LI8"
FT MOD_RES 329
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q99LI8"
FT MOD_RES 334
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q99LI8"
FT MOD_RES 550
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q99LI8"
FT VAR_SEQ 671..675
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9798906"
FT /id="VSP_014852"
FT CONFLICT 394
FT /note="Missing (in Ref. 1; AAB49681)"
FT /evidence="ECO:0000305"
FT CONFLICT 398
FT /note="G -> A (in Ref. 4; AAH83561)"
FT /evidence="ECO:0000305"
FT CONFLICT 561
FT /note="A -> V (in Ref. 4; AAH83561)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 776 AA; 86246 MW; FD61BEC121F37E67 CRC64;
MGRGSGTFER LLDKATSQLL LETDWESILQ ICDLIRQGDT QAKYAVNSIK KKVNDKNPHV
ALYALEVMES VVKNCGQTVH DEVANKQTME ELKELLKRQV EVNVRNKILY LIQAWAHAFR
NEPKYKVVQD TYQIMKVEGH VFPEFKESDA MFAAERAPDW VDAEECHRCR VQFGVVTRKH
HCRACGQIFC GKCSSKYSTI PKFGIEKEVR VCEPCYEQLN KKAEGKAAST TELPPEYLTS
PLSQQSQLPP KRDETALQEE EELQLALALS QSEAEEKERM RQKSTYTAHP KSEPAPLASS
APPAGSLYSS PVNSSAPLAE DIDPELARYL NRNYWEKKQE EARKSPTPSA PVPLTEPAAQ
PGEGHTAPNS MVEAPLPETD SQPITSCSGP FSEQYQNGES EESHEQFLKA LQNAVSTFVN
RMKSNHMRGR SITNDSAVLS LFQSINSTHP QLLELLNRLD ERRLYYEGLQ DKLAQIRDAR
GALSALREEH REKLRRAAEE AERQRQIQLA QKLEIMRQKK QEYLEVQRQL AIQRLQEQEK
ERQMRLEQQK QTVQMRAQMP AFPLPYAQLQ AMPTAGGVLY QPSGPTSFPG TFSPAGSVEG
SPMHGVYMSQ PAPATGPYPS MPGTTADPSM VSAYMYPAGA PGAQAAPQAQ AGPTTNPAYS
SYQPTPTPGY QNVASQAPQS LPAISQPPQT SNIGYMGSQP MSMGYQPYNM QNLMTTLPGQ
DASLPAQQPY ITGQQPMYQQ MAPSTGPPQQ QPPVAQPPPT QGPPAQGNET QLISFD
