RBCC

Full text data of HGS

HGS (HRS) [Confidence: low (only semi-automatic identification from reviews)]
Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs; Protein pp110)

UniProt O14964
ID HGS_HUMAN Reviewed; 777 AA.
AC O14964; Q9NR36;
DT 19-JUL-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1998, sequence version 1.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Hepatocyte growth factor-regulated tyrosine kinase substrate;
DE AltName: Full=Hrs;
DE AltName: Full=Protein pp110;
GN Name=HGS; Synonyms=HRS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP INTERACTION WITH STAM.
RX PubMed=9407053; DOI=10.1074/jbc.272.52.32785;
RA Asao H., Sasaki Y., Arita T., Tanaka N., Endo K., Kasai H.,
RA Takeshita T., Endo Y., Fujita T., Sugamura K.;
RT "Hrs is associated with STAM, a signal-transducing adaptor molecule.
RT Its suppressive effect on cytokine-induced cell growth.";
RL J. Biol. Chem. 272:32785-32791(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Placenta;
RX PubMed=9630564; DOI=10.1016/S0378-1119(98)00184-X;
RA Lu L., Komada M., Kitamura N.;
RT "Human Hrs, a tyrosine kinase substrate in growth factor-stimulated
RT cells: cDNA cloning and mapping of the gene to chromosome 17.";
RL Gene 213:125-132(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), DOMAIN, INTERACTION WITH NF2,
RP AND SUBCELLULAR LOCATION.
RC TISSUE=Brain;
RX PubMed=10861283; DOI=10.1093/hmg/9.11.1567;
RA Scoles D.R., Huynh D.P., Chen M.S., Burke S.P., Gutmann D.H.,
RA Pulst S.-M.;
RT "The neurofibromatosis 2 tumor suppressor protein interacts with
RT hepatocyte growth factor-regulated tyrosine kinase substrate.";
RL Hum. Mol. Genet. 9:1567-1574(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP SUBCELLULAR LOCATION.
RX PubMed=9252367; DOI=10.1074/jbc.272.33.20538;
RA Komada M., Masaki R., Yamamoto A., Kitamura N.;
RT "Hrs, a tyrosine kinase substrate with a conserved double zinc finger
RT domain, is localized to the cytoplasmic surface of early endosomes.";
RL J. Biol. Chem. 272:20538-20544(1997).
RN [7]
RP UBIQUITINATION BY ITCH.
RX PubMed=14602072; DOI=10.1016/S1534-5807(03)00321-6;
RA Marchese A., Raiborg C., Santini F., Keen J.H., Stenmark H.,
RA Benovic J.L.;
RT "The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of
RT the G protein-coupled receptor CXCR4.";
RL Dev. Cell 5:709-722(2003).
RN [8]
RP INTERACTION WITH STAM; STAM2 AND EPS15, AND IDENTIFICATION IN A
RP COMPLEX WITH STAM2 AND EPS15.
RX PubMed=12551915; DOI=10.1074/jbc.M210843200;
RA Bache K.G., Raiborg C., Mehlum A., Stenmark H.;
RT "STAM and Hrs are subunits of a multivalent ubiquitin-binding complex
RT on early endosomes.";
RL J. Biol. Chem. 278:12513-12521(2003).
RN [9]
RP INTERACTION WITH HIV-1 GAG AND HGS, AND SELF-ASSOCIATION.
RX PubMed=12900394; DOI=10.1083/jcb.200302138;
RA Pornillos O., Higginson D.S., Stray K.M., Fisher R.D., Garrus J.E.,
RA Payne M., He G.P., Wang H.E., Morham S.G., Sundquist W.I.;
RT "HIV Gag mimics the Tsg101-recruiting activity of the human Hrs
RT protein.";
RL J. Cell Biol. 162:425-434(2003).
RN [10]
RP INTERACTION WITH VPS37C.
RX PubMed=15509564; DOI=10.1074/jbc.M410384200;
RA Eastman S.W., Martin-Serrano J., Chung W., Zang T., Bieniasz P.D.;
RT "Identification of human VPS37C, a component of endosomal sorting
RT complex required for transport-I important for viral budding.";
RL J. Biol. Chem. 280:628-636(2005).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-216, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [13]
RP INTERACTION WITH TRAK1.
RX PubMed=18675823; DOI=10.1016/j.jmb.2008.07.045;
RA Webber E., Li L., Chin L.S.;
RT "Hypertonia-associated protein Trak1 is a novel regulator of endosome-
RT to-lysosome trafficking.";
RL J. Mol. Biol. 382:638-651(2008).
RN [14]
RP IDENTIFICATION IN THE CART COMPLEX.
RX PubMed=15772161; DOI=10.1091/mbc.E04-11-1014;
RA Yan Q., Sun W., Kujala P., Lotfi Y., Vida T.A., Bean A.J.;
RT "CART: an Hrs/actinin-4/BERP/myosin V protein complex required for
RT efficient receptor recycling.";
RL Mol. Biol. Cell 16:2470-2482(2005).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [17]
RP DOMAIN FYVE-TYPE ZINC FINGER.
RX PubMed=19296456; DOI=10.1002/prot.22392;
RA He J., Vora M., Haney R.M., Filonov G.S., Musselman C.A., Burd C.G.,
RA Kutateladze A.G., Verkhusha V.V., Stahelin R.V., Kutateladze T.G.;
RT "Membrane insertion of the FYVE domain is modulated by pH.";
RL Proteins 76:852-860(2009).
RN [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-207, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 257-277 IN COMPLEX WITH
RP UBIQUITIN, AND MUTAGENESIS OF ALA-266 AND ALA-268.
RX PubMed=16462748; DOI=10.1038/nsmb1051;
RA Hirano S., Kawasaki M., Ura H., Kato R., Raiborg C., Stenmark H.,
RA Wakatsuki S.;
RT "Double-sided ubiquitin binding of Hrs-UIM in endosomal protein
RT sorting.";
RL Nat. Struct. Mol. Biol. 13:272-277(2006).
RN [22]
RP VARIANT [LARGE SCALE ANALYSIS] SER-7.
RX PubMed=18987736; DOI=10.1038/nature07485;
RA Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K.,
RA Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L.,
RA Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A.,
RA Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V.,
RA Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R.,
RA Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E.,
RA Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J.,
RA Heath S., Shannon W.D., Nagarajan R., Walter M.J., Link D.C.,
RA Graubert T.A., DiPersio J.F., Wilson R.K.;
RT "DNA sequencing of a cytogenetically normal acute myeloid leukaemia
RT genome.";
RL Nature 456:66-72(2008).
CC -!- FUNCTION: Involved in intracellular signal transduction mediated
CC by cytokines and growth factors. When associated with STAM, it
CC suppresses DNA signaling upon stimulation by IL-2 and GM-CSF.
CC Could be a direct effector of PI3-kinase in vesicular pathway via
CC early endosomes and may regulate trafficking to early and late
CC endosomes by recruiting clathrin. May concentrate ubiquitinated
CC receptors within clathrin-coated regions. Involved in down-
CC regulation of receptor tyrosine kinase via multivesicular body
CC (MVBs) when complexed with STAM (ESCRT-0 complex). The ESCRT-0
CC complex binds ubiquitin and acts as sorting machinery that
CC recognizes ubiquitinated receptors and transfers them to further
CC sequential lysosomal sorting/trafficking processes. May contribute
CC to the efficient recruitment of SMADs to the activin receptor
CC complex. Involved in receptor recycling via its association with
CC the CART complex, a multiprotein complex required for efficient
CC transferrin receptor recycling but not for EGFR degradation.
CC -!- SUBUNIT: Interacts with TRAK1. Interacts with TRAK2 (By
CC similarity). Interacts with TRAK1. Component of the ESCRT-0
CC complex composed of STAM or STAM2 and HGS. Part of a complex at
CC least composed of HSG, STAM2 (or probably STAM) and EPS15.
CC Interacts with STAM. Interacts with STAM2. Interacts with EPS15;
CC the interaction is direct, calcium-dependent and inhibited by
CC SNAP25. Interacts with NF2; the interaction is direct. Interacts
CC with ubiquitin; the interaction is direct. Interacts with VPS37C.
CC Interacts with SMAD1, SMAD2 and SMAD3. Interacts with TSG101; the
CC interaction mediates the association with the ESCRT-I complex.
CC Interacts with SNAP25; the interaction is direct and decreases
CC with addition of increasing concentrations of free calcium.
CC Interacts with SNX1; the interaction is direct. Component of a 550
CC kDa membrane complex at least composed of HGS and SNX1 but
CC excluding EGFR. Component of the CART complex, at least composed
CC of ACTN4, HGS/HRS, MYO5B and TRIM3.
CC -!- INTERACTION:
CC Q6NRD3:sh3rf1 (xeno); NbExp=3; IntAct=EBI-740220, EBI-7734031;
CC P0CG53:UBB (xeno); NbExp=7; IntAct=EBI-740220, EBI-5333021;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Early endosome membrane;
CC Peripheral membrane protein; Cytoplasmic side. Endosome,
CC multivesicular body membrane; Peripheral membrane protein (By
CC similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=HRSi1;
CC IsoId=O14964-1; Sequence=Displayed;
CC Name=2; Synonyms=HRSi2;
CC IsoId=O14964-2; Sequence=VSP_036172;
CC Note=Dubious isoform produced through aberrant splice sites;
CC -!- TISSUE SPECIFICITY: Ubiquitous expression in adult and fetal
CC tissues with higher expression in testis and peripheral blood
CC leukocytes.
CC -!- DOMAIN: Has a double-sided UIM that can bind 2 ubiquitin
CC molecules, one on each side of the helix.
CC -!- DOMAIN: The FYVE-type zinc finger domain mediates interactions
CC with phosphatidylinositol 3-phosphate in membranes of early
CC endosomes and penetrates bilayers. The FYVE domain insertion into
CC PtdIns(3)P-enriched membranes is substantially increased in acidic
CC conditions.
CC -!- PTM: Phosphorylated on Tyr-334. A minor site of phosphorylation on
CC Tyr-329 is detected (By similarity). Phosphorylation occurs in
CC response to EGF, IL-2, GM-CSF and HGF.
CC -!- PTM: Ubiquitinated by ITCH.
CC -!- SIMILARITY: Contains 1 FYVE-type zinc finger.
CC -!- SIMILARITY: Contains 1 UIM (ubiquitin-interacting motif) repeat.
CC -!- SIMILARITY: Contains 1 VHS domain.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U43895; AAC51929.1; -; mRNA.
DR EMBL; D84064; BAA23366.1; -; mRNA.
DR EMBL; AF260566; AAF82361.1; -; mRNA.
DR EMBL; BT009754; AAP88756.1; -; mRNA.
DR EMBL; BC003565; AAH03565.1; -; mRNA.
DR RefSeq; NP_004703.1; NM_004712.4.
DR UniGene; Hs.661056; -.
DR PDB; 2D3G; X-ray; 1.70 A; P=257-277.
DR PDB; 3F1I; X-ray; 2.30 A; H=404-501.
DR PDB; 3OBQ; X-ray; 1.40 A; B=346-354.
DR PDB; 3ZYQ; X-ray; 1.48 A; A=1-225.
DR PDB; 4AVX; X-ray; 1.68 A; A=1-225.
DR PDBsum; 2D3G; -.
DR PDBsum; 3F1I; -.
DR PDBsum; 3OBQ; -.
DR PDBsum; 3ZYQ; -.
DR PDBsum; 4AVX; -.
DR ProteinModelPortal; O14964; -.
DR SMR; O14964; 6-221, 404-501.
DR DIP; DIP-29050N; -.
DR IntAct; O14964; 49.
DR MINT; MINT-234372; -.
DR STRING; 9606.ENSP00000331201; -.
DR PhosphoSite; O14964; -.
DR PaxDb; O14964; -.
DR PeptideAtlas; O14964; -.
DR PRIDE; O14964; -.
DR DNASU; 9146; -.
DR Ensembl; ENST00000329138; ENSP00000331201; ENSG00000185359.
DR GeneID; 9146; -.
DR KEGG; hsa:9146; -.
DR UCSC; uc002kbg.3; human.
DR CTD; 9146; -.
DR GeneCards; GC17P079651; -.
DR HGNC; HGNC:4897; HGS.
DR HPA; HPA004872; -.
DR HPA; HPA007728; -.
DR MIM; 604375; gene.
DR neXtProt; NX_O14964; -.
DR PharmGKB; PA29271; -.
DR eggNOG; NOG257212; -.
DR HOGENOM; HOG000044175; -.
DR HOVERGEN; HBG062917; -.
DR InParanoid; O14964; -.
DR KO; K12182; -.
DR OMA; ERMRQKS; -.
DR OrthoDB; EOG7N37CN; -.
DR PhylomeDB; O14964; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_116125; Disease.
DR SignaLink; O14964; -.
DR ChiTaRS; HGS; human.
DR EvolutionaryTrace; O14964; -.
DR GeneWiki; HGS_(gene); -.
DR GenomeRNAi; 9146; -.
DR NextBio; 34307; -.
DR PRO; PR:O14964; -.
DR ArrayExpress; O14964; -.
DR Bgee; O14964; -.
DR CleanEx; HS_HGS; -.
DR Genevestigator; O14964; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005769; C:early endosome; IDA:HGNC.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0032585; C:multivesicular body membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030141; C:secretory granule; IEA:Ensembl.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0016197; P:endosomal transport; NAS:UniProtKB.
DR GO; GO:0008333; P:endosome to lysosome transport; IEA:Ensembl.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0006886; P:intracellular protein transport; IEA:InterPro.
DR GO; GO:0008285; P:negative regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0046426; P:negative regulation of JAK-STAT cascade; IDA:HGNC.
DR GO; GO:0042176; P:regulation of protein catabolic process; TAS:HGNC.
DR Gene3D; 1.25.40.90; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR008942; ENTH_VHS.
DR InterPro; IPR027426; HGS.
DR InterPro; IPR024641; HRS_helical.
DR InterPro; IPR017073; Ubi-bd_Hrs_VPS27.
DR InterPro; IPR003903; Ubiquitin-int_motif.
DR InterPro; IPR002014; VHS.
DR InterPro; IPR018205; VHS_subgr.
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; PTHR13856:SF45; PTHR13856:SF45; 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; SM00726; UIM; 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 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Endosome; Membrane; Metal-binding; Phosphoprotein;
KW Polymorphism; Protein transport; Reference proteome; Transport;
KW Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1 777 Hepatocyte growth factor-regulated
FT tyrosine kinase substrate.
FT /FTId=PRO_0000098708.
FT DOMAIN 15 143 VHS.
FT REPEAT 258 277 UIM.
FT ZN_FING 160 220 FYVE-type.
FT REGION 225 543 Interaction with SNX1 (By similarity).
FT REGION 445 543 Interaction with SNAP25 and TRAK2 (By
FT similarity).
FT REGION 454 572 Interaction with STAM1 (By similarity).
FT REGION 480 777 Interaction with NF2.
FT COMPBIAS 346 394 Pro-rich.
FT COMPBIAS 505 772 Gln-rich.
FT MOD_RES 207 207 N6-acetyllysine.
FT MOD_RES 216 216 Phosphotyrosine.
FT MOD_RES 308 308 Phosphotyrosine (By similarity).
FT MOD_RES 329 329 Phosphotyrosine (By similarity).
FT MOD_RES 334 334 Phosphotyrosine (By similarity).
FT VAR_SEQ 518 604 Missing (in isoform 2).
FT /FTId=VSP_036172.
FT VARIANT 7 7 T -> S.
FT /FTId=VAR_054154.
FT VARIANT 400 400 E -> D (in dbSNP:rs34868130).
FT /FTId=VAR_052981.
FT VARIANT 733 733 A -> S (in dbSNP:rs56058441).
FT /FTId=VAR_061991.
FT MUTAGEN 266 266 A->Q: Strongly reduced ubiquitin-binding.
FT Reduced degradation of ubiquitinated
FT EGFR.
FT MUTAGEN 268 268 A->Q: Strongly reduced ubiquitin-binding.
FT Reduced degradation of ubiquitinated
FT EGFR.
FT CONFLICT 236 236 E -> D (in Ref. 3; AAF82361).
FT HELIX 7 15
FT HELIX 25 36
FT HELIX 42 53
FT HELIX 58 75
FT HELIX 77 83
FT HELIX 86 98
FT HELIX 102 118
FT TURN 119 121
FT HELIX 123 125
FT HELIX 126 138
FT HELIX 147 150
FT TURN 167 169
FT TURN 183 185
FT TURN 191 193
FT STRAND 196 200
FT HELIX 201 203
FT STRAND 205 211
FT HELIX 213 219
FT HELIX 258 273
FT HELIX 405 428
FT HELIX 433 435
FT HELIX 437 499
SQ SEQUENCE 777 AA; 86192 MW; DD64167A19DCF030 CRC64;
MGRGSGTFER LLDKATSQLL LETDWESILQ ICDLIRQGDT QAKYAVNSIK KKVNDKNPHV
ALYALEVMES VVKNCGQTVH DEVANKQTME ELKDLLKRQV EVNVRNKILY LIQAWAHAFR
NEPKYKVVQD TYQIMKVEGH VFPEFKESDA MFAAERAPDW VDAEECHRCR VQFGVMTRKH
HCRACGQIFC GKCSSKYSTI PKFGIEKEVR VCEPCYEQLN RKAEGKATST TELPPEYLTS
PLSQQSQLPP KRDETALQEE EELQLALALS QSEAEEKERL RQKSTYTSYP KAEPMPSASS
APPASSLYSS PVNSSAPLAE DIDPELARYL NRNYWEKKQE EARKSPTPSA PVPLTEPAAQ
PGEGHAAPTN VVENPLPETD SQPIPPSGGP FSEPQFHNGE SEESHEQFLK ALQNAVTTFV
NRMKSNHMRG RSITNDSAVL SLFQSINGMH PQLLELLNQL DERRLYYEGL QDKLAQIRDA
RGALSALREE HREKLRRAAE EAERQRQIQL AQKLEIMRQK KQEYLEVQRQ LAIQRLQEQE
KERQMRLEQQ KQTVQMRAQM PAFPLPYAQL QAMPAAGGVL YQPSGPASFP STFSPAGSVE
GSPMHGVYMS QPAPAAGPYP SMPSTAADPS MVSAYMYPAG ATGAQAAPQA QAGPTASPAY
SSYQPTPTAG YQNVASQAPQ SLPAISQPPQ SSTMGYMGSQ SVSMGYQPYN MQNLMTTLPS
QDASLPPQQP YIAGQQPMYQ QMAPSGGPPQ QQPPVAQQPQ AQGPPAQGSE AQLISFD
//

MIM 604375
*RECORD*
*FIELD* NO
604375
*FIELD* TI
*604375 HUMAN GROWTH FACTOR-REGULATED TYROSINE KINASE SUBSTRATE; HGS
;;HEPATOCYTE GROWTH FACTOR-REGULATED TYROSINE KINASE SUBSTRATE; HRS;;
read moreHGF-REGULATED TYROSINE KINASE SUBSTRATE
*FIELD* TX
Activation of tyrosine kinases is an initial biochemical event in
intracellular signal transduction from cytokine receptors after their
binding with ligands. Several families of tyrosine kinases are known to
be associated with the cytoplasmic domains of cytokine receptors. Upon
activation of tyrosine kinases, cytokine receptor subunits are
phosphorylated on tyrosine residues, which results in association of the
receptor subunits with signal transducers and activators of
transcription, or STATs.

Asao et al. (1997) cloned a 110-kD phosphotyrosine protein inducible by
stimulation with interleukin-2 (IL2; 147680). They isolated a cDNA clone
for the pp110 from the MOLT-beta T-cell line. The deduced amino acid
sequence of HGS, which the authors symbolized HRS, was found to be 93%
homologous to that of mouse Hrs. HGS contains double zinc finger (FYVE)
motifs, a putative coiled-coil sequence, and nucleotide-binding sites.
Northern blot analysis detected expression of HGS in lymphoid and
nonlymphoid tissues. Immunoblotting, however, determined that the
phosphorylated species was found after but not before IL2 stimulation.
Irrespective of IL2 stimulation, HGS coimmunoprecipitated with STAM
(601899), a signal-transducing adaptor molecule that is directly
associated with and phosphorylated by JAK3 and JAK2 upon stimulation
with IL2 and GMCSF (138960), respectively. A mouse Hrs mutant from which
the coiled-coil sequence was deleted lost STAM binding activity.
Likewise, a mutant of STAM, lacking part of the coiled-coil sequence,
had only weak binding to HGS. The IL2 receptor- or GMCSF
receptor-bearing cells transfected with wildtype HGS were inhibited in a
dose-dependent manner from proliferating in response to cytokine
stimulation by up to 76% and 73%, respectively. Mutant HGS without the
coiled-coil sequence failed to inhibit proliferation.

Lu et al. (1998) cloned a full-length HGS cDNA from a human placenta
cDNA library by cross-hybridization, using the mouse Hrs cDNA as a
probe. They determined that the cDNA encodes a deduced 777-amino acid
protein. Northern blot analysis showed that a 3.0-kb transcript of HGS
was present in all adult and fetal tissues tested, with highest
expression in testis and peripheral blood leukocytes.

By fluorescence in situ hybridization, Asao et al. (1997) mapped the HGS
gene to chromosome 17q25. Lu et al. (1998) mapped the HGS gene to
chromosome 17 by somatic cell hybridization.

Komada et al. (1997) showed that Hrs is localized to the cytoplasmic
surface of early endosomes. Komada and Soriano (1999) generated mice
carrying a null mutation of the Hrs gene. Homozygous mutant mouse
embryos exhibit a defect in ventral folding morphogenesis and die around
embryonic day 11. Komada and Soriano (1999) observed abnormally enlarged
early endosomes in the mutants in several tissues including definitive
endoderm, suggesting that a deficiency in vesicular transport via early
endosomes underlies the phenotype.

Using yeast 2-hybrid interaction cloning, Scoles et al. (2000)
determined that schwannomin (NF2; 607379) interacts with the
HGF-regulated tyrosine kinase substrate. They demonstrated the
interaction both in vivo, by immunoprecipitation of endogenous HRS with
endogenous schwannomin, and in vitro, with a binding assay using
bacterially purified HRS and schwannomin. The regions of interaction
included schwannomin residues 256 to 579 and HRS residues from 480 to
the end of either of 2 HRS isoforms. Schwannomin molecules with an L46R,
L360P, L535P, or Q538P missense mutation demonstrated reduced affinity
for HRS binding. Since HRS is associated with early endosomes and may
mediate receptor translocation to the lysosome, the authors used
indirect immunofluorescence to demonstrate that schwannomin and HRS
colocalize at endosomes in STS26T Schwann cells. The authors
hypothesized that schwannomin is involved in HRS-mediated cell
signaling.

Gutmann et al. (2001) demonstrated that regulated overexpression of HRS
in rat schwannoma cells yields effects similar to those seen with
overexpression of merlin (or schwannomin), including growth inhibition,
decreased motility, and abnormalities in cell spreading. The HRS binding
domain of merlin was mapped to residues 453-557. Overexpression of
C-terminal merlin had no effect on HRS function, suggesting to the
authors that merlin binding to HRS does not negatively regulate HRS
growth suppressor activity, and that merlin and HRS may regulate cell
growth in schwannoma cells through interacting pathways.

Sun et al. (2002) generated a series of HRS truncation mutants to define
the regions required for merlin binding and HRS growth suppression. The
HRS domain required for merlin binding was narrowed to residues 470-497
(which contain the predicted coiled-coil domain), and the major domain
responsible for HRS growth suppression was localized to residues
498-550. Merlin inhibited growth in Hrs +/+, but not Hrs -/- mouse
embryonic fibroblast cells. In contrast, HRS could suppress cell growth
in the absence of Nf2 expression. The authors concluded that merlin
growth suppression requires HRS expression, and that the binding of
merlin to HRS may facilitate its ability to function as a tumor
suppressor.

Using transient transfection methods, Scoles et al. (2002) showed that
both schwannomin and HRS inhibited STAT3 (102582) activation, and
schwannomin suppressed STAT3 activation mediated by IGF1 (147440)
treatment in a human schwannoma cell line. Schwannomin inhibited STAT3
and STAT5 (601511) phosphorylation in a rat schwannoma cell line.
Schwannomin with the pathogenic missense mutation Q538P (607379.0006)
failed to bind HRS and did not inhibit STAT5 phosphorylation. The
authors hypothesized that schwannomin requires HRS interaction to be
fully functionally active and to inhibit STAT activation.

Marchese et al. (2003) determined that AIP4 (606409) colocalized with
CXCR4 (162643) at the plasma membrane in transfected HEK293 cells and
that it colocalized with HRS on endosomes in transfected HeLa cells.
AIP4, HRS, and a vacuole sorting protein, VPS4, were required for
targeting CXCR4 to the degradative pathway.

*FIELD* RF
1. Asao, H.; Sasaki, Y.; Arita, T.; Tanaka, N.; Endo, K.; Kasai, H.;
Takeshita, T; Endo, Y.; Fujita, T.; Sugamura, K.: Hrs is associated
with STAM, a signal-transducing adaptor molecule: its suppressive
effect on cytokine-induced cell growth. J. Biol. Chem. 272: 32785-32791,
1997.

2. Gutmann, D. H.; Haipek, C. A.; Burke, S. P.; Sun, C.-X.; Scoles,
D. R.; Pulst, S. M.: The NF2 interactor, hepatocyte growth factor-regulated
tyrosine kinase substrate (HRS), associates with merlin in the 'open'
conformation and suppresses cell growth and motility. Hum. Molec.
Genet. 10: 825-834, 2001.

3. Komada, M.; Masaki, R.; Yamamoto, A.; Kitamura, N.: Hrs, a tyrosine
kinase substrate with a conserved double zinc finger domain, is localized
to the cytoplasmic surface of early endosomes. J. Biol. Chem. 272:
20538-20544, 1997.

4. Komada, M.; Soriano, P.: Hrs, a FYVE finger protein localized
to early endosomes, is implicated in vesicular traffic and required
for ventral folding morphogenesis. Genes Dev. 13: 1475-1485, 1999.

5. Lu, L.; Komada, M.; Kitamura, N.: Human Hrs, a tyrosine kinase
substrate in growth factor-stimulated cells: cDNA cloning and mapping
of the gene to chromosome 17. Gene 213: 125-132, 1998.

6. Marchese, A.; Raiborg, C.; Santini, F.; Keen, J. H.; Stenmark,
H.; Benovic, J. L.: The E3 ubiquitin ligase AIP4 mediates ubiquitination
and sorting of the G protein-coupled receptor CXCR4. Dev. Cell 5:
709-722, 2003.

7. Scoles, D. R.; Huynh, D. P.; Chen, M. S.; Burke, S. P.; Gutmann,
D. H.; Pulst, S.-M.: The neurofibromatosis 2 tumor suppressor protein
interacts with hepatocyte growth factor-regulated tyrosine kinase
substrate. Hum. Molec. Genet. 9: 1567-1574, 2000.

8. Scoles, D. R.; Nguyen, V. D.; Qin, Y.; Sun, C.-X.; Morrison, H.;
Gutmann, D. H.; Pulst, S.-M.: Neurofibromatosis 2 (NF2) tumor suppressor
schwannomin and its interacting protein HRS regulate STAT signaling. Hum.
Molec. Genet. 11: 3179-3189, 2002.

9. Sun, C.-X.; Haipek, C.; Scoles, D. R.; Pulst, S. M.; Giovannini,
M.; Komada, M.; Gutmann, D. H.: Functional analysis of the relationship
between the neurofibromatosis 2 tumor suppressor and its binding partner,
hepatocyte growth factor-regulated tyrosine kinase substrate. Hum.
Molec. Genet. 11: 3167-3178, 2002.

*FIELD* CN
George E. Tiller - updated: 9/2/2004
Patricia A. Hartz - updated: 5/13/2004
George E. Tiller - updated: 7/23/2001
George E. Tiller - updated: 9/13/2000

*FIELD* CD
Paul J. Converse: 12/27/1999

*FIELD* ED
carol: 09/03/2004
terry: 9/2/2004
mgross: 5/13/2004
carol: 1/28/2003
cwells: 7/27/2001
cwells: 7/23/2001
alopez: 9/13/2000
carol: 12/28/1999

RBCC Red Blood Cell Collection

Full text data of HGS