GHR_RABIT
ID GHR_RABIT Reviewed; 638 AA.
AC P19941;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1991, sequence version 1.
DT 25-MAY-2022, entry version 155.
DE RecName: Full=Growth hormone receptor;
DE Short=GH receptor;
DE AltName: Full=Somatotropin receptor;
DE Contains:
DE RecName: Full=Growth hormone-binding protein;
DE Short=GH-binding protein;
DE Short=GHBP;
DE AltName: Full=Serum-binding protein;
DE Flags: Precursor;
GN Name=GHR;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=2825030; DOI=10.1038/330537a0;
RA Leung D.W., Spencer S.A., Cachianes G., Hammonds R.G., Collins C.,
RA Henzel W.J., Barnard R., Waters M.J., Wood W.I.;
RT "Growth hormone receptor and serum binding protein: purification, cloning
RT and expression.";
RL Nature 330:537-543(1987).
RN [2]
RP GHBP SHEDDING SITE, AND SUBCELLULAR LOCATION.
RX PubMed=12403792; DOI=10.1074/jbc.m208738200;
RA Wang X., He K., Gerhart M., Huang Y., Jiang J., Paxton R.J., Yang S.,
RA Lu C., Menon R.K., Black R.A., Baumann G., Frank S.J.;
RT "Metalloprotease-mediated GH receptor proteolysis and GHBP shedding.
RT Determination of extracellular domain stem region cleavage site.";
RL J. Biol. Chem. 277:50510-50519(2002).
RN [3]
RP INTERACTION WITH ADAM17.
RX PubMed=14519102; DOI=10.1042/bj20031321;
RA Schantl J.A., Roza M., Van Kerkhof P., Strous G.J.;
RT "The growth hormone receptor interacts with its sheddase, the tumour
RT necrosis factor-alpha-converting enzyme (TACE).";
RL Biochem. J. 377:379-384(2004).
RN [4]
RP UBIQUITINATION-DEPENDENT ENDOCYTOSIS MOTIF, AND MUTAGENESIS OF ASN-338;
RP ASP-339; ASP-340; SER-341; TRP-342; VAL-343; GLU-344; PHE-345; ILE-346;
RP GLU-347; LEU-348; ASP-349; ILE-350; ASP-351 AND ASP-352.
RX PubMed=9878047; DOI=10.1093/emboj/18.1.28;
RA Govers R., ten Broeke T., van Kerkhof P., Schwartz A.L., Strous G.J.;
RT "Identification of a novel ubiquitin conjugation motif, required for
RT ligand-induced internalization of the growth hormone receptor.";
RL EMBO J. 18:28-36(1999).
RN [5]
RP PROTEOLYTIC PROCESSING BY ADAM17.
RX PubMed=11108241; DOI=10.1210/endo.141.12.7858;
RA Zhang Y., Jiang J., Black R.A., Baumann G., Frank S.J.;
RT "Tumor necrosis factor-alpha converting enzyme (TACE) is a growth hormone
RT binding protein (GHBP) sheddase: the metalloprotease TACE/ADAM-17 is
RT critical for (PMA-induced) GH receptor proteolysis and GHBP generation.";
RL Endocrinology 141:4342-4348(2000).
RN [6]
RP UBIQUITINATION, ENDOCYTOSIS, AND DEGRADATION.
RX PubMed=11418602; DOI=10.1074/jbc.m103583200;
RA Alves dos Santos C.M., ten Broeke T., Strous G.J.;
RT "Growth hormone receptor ubiquitination, endocytosis, and degradation are
RT independent of signal transduction via Janus kinase 2.";
RL J. Biol. Chem. 276:32635-32641(2001).
CC -!- FUNCTION: Receptor for pituitary gland growth hormone involved in
CC regulating postnatal body growth. On ligand binding, couples to, and
CC activates the JAK2/STAT5 pathway (By similarity). {ECO:0000250}.
CC -!- FUNCTION: The soluble form (GHBP) acts as a reservoir of growth hormone
CC in plasma and may be a modulator/inhibitor of GH signaling.
CC -!- SUBUNIT: On growth hormone (GH) binding, forms homodimers and binds
CC JAK2 via a box 1-containing domain (By similarity). Binding to SOCS3
CC inhibits JAK2 activation, binding to CIS and SOCS2 inhibits STAT5
CC activation (By similarity). Interacts with ADAM17. {ECO:0000250,
CC ECO:0000269|PubMed:14519102}.
CC -!- INTERACTION:
CC P19941; P42230: Stat5a; Xeno; NbExp=3; IntAct=EBI-7526279, EBI-617434;
CC P19941; P42232: Stat5b; Xeno; NbExp=6; IntAct=EBI-7526279, EBI-617454;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I
CC membrane protein {ECO:0000250}. Note=On growth hormone binding, GHR is
CC ubiquitinated, internalized, down-regulated and transported into a
CC degradative or non-degradative pathway. {ECO:0000269|PubMed:12403792}.
CC -!- SUBCELLULAR LOCATION: [Growth hormone-binding protein]: Secreted.
CC Note=Complexed to a substantial fraction of circulating GH.
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-surface
CC receptor binding.
CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or
CC activation.
CC -!- DOMAIN: The extracellular domain is the ligand-binding domain
CC representing the growth hormone-binding protein (GHBP).
CC -!- DOMAIN: The ubiquitination-dependent endocytosis motif (UbE) is
CC required for recruitment of the ubiquitin conjugation system on to the
CC receptor and for its internalization.
CC -!- PTM: The soluble form (GHBP) is produced by phorbol ester-promoted
CC proteolytic cleavage at the cell surface (shedding) by ADAM17/TACE.
CC Shedding is inhibited by growth hormone (GH) binding to the receptor
CC probably due to a conformational change in GHR rendering the receptor
CC inaccessible to ADAM17. {ECO:0000269|PubMed:11108241}.
CC -!- PTM: On GH binding, phosphorylated on tyrosine residues in the
CC cytoplasmic domain by JAK2. {ECO:0000250}.
CC -!- PTM: On ligand binding, ubiquitinated on lysine residues in the
CC cytoplasmic domain. This ubiquitination is not sufficient for GHR
CC internalization. {ECO:0000269|PubMed:11418602,
CC ECO:0000269|PubMed:9878047}.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 1
CC subfamily. {ECO:0000305}.
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DR EMBL; AF015252; AAB67613.1; -; mRNA.
DR PIR; S08544; B28176.
DR RefSeq; NP_001076105.1; NM_001082636.1.
DR AlphaFoldDB; P19941; -.
DR SMR; P19941; -.
DR BioGRID; 1172345; 4.
DR DIP; DIP-313N; -.
DR IntAct; P19941; 4.
DR MINT; P19941; -.
DR STRING; 9986.ENSOCUP00000007343; -.
DR iPTMnet; P19941; -.
DR GeneID; 100009325; -.
DR KEGG; ocu:100009325; -.
DR CTD; 2690; -.
DR eggNOG; KOG3555; Eukaryota.
DR InParanoid; P19941; -.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0031904; C:endosome lumen; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0016021; C:integral component of membrane; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0004896; F:cytokine receptor activity; IEA:InterPro.
DR GO; GO:0017046; F:peptide hormone binding; IPI:BHF-UCL.
DR GO; GO:0070064; F:proline-rich region binding; IPI:BHF-UCL.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0060396; P:growth hormone receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IDA:BHF-UCL.
DR CDD; cd00063; FN3; 1.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR025871; GHBP.
DR InterPro; IPR015152; Growth/epo_recpt_lig-bind.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003528; Long_hematopoietin_rcpt_CS.
DR Pfam; PF09067; EpoR_lig-bind; 1.
DR Pfam; PF00041; fn3; 1.
DR Pfam; PF12772; GHBP; 1.
DR SMART; SM00060; FN3; 1.
DR SUPFAM; SSF49265; SSF49265; 2.
DR PROSITE; PS50853; FN3; 1.
DR PROSITE; PS01352; HEMATOPO_REC_L_F1; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Direct protein sequencing; Disulfide bond; Endocytosis;
KW Glycoprotein; Membrane; Phosphoprotein; Receptor; Reference proteome;
KW Secreted; Signal; Transmembrane; Transmembrane helix; Ubl conjugation.
FT SIGNAL 1..18
FT CHAIN 19..638
FT /note="Growth hormone receptor"
FT /id="PRO_0000010967"
FT CHAIN 19..256
FT /note="Growth hormone-binding protein"
FT /id="PRO_0000010968"
FT TOPO_DOM 19..264
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 265..288
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 289..638
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 151..254
FT /note="Fibronectin type-III"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT REGION 30..51
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 260..262
FT /note="Required for ADAM17-mediated proteolysis"
FT REGION 294..379
FT /note="Required for JAK2 binding"
FT /evidence="ECO:0000250"
FT REGION 573..592
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 240..244
FT /note="WSXWS motif"
FT MOTIF 297..305
FT /note="Box 1 motif"
FT MOTIF 340..349
FT /note="UbE motif"
FT SITE 345
FT /note="Required for endocytosis and down-regulation"
FT MOD_RES 341
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P10912"
FT CARBOHYD 46
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 156
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 161
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 200
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 56..66
FT /evidence="ECO:0000250"
FT DISULFID 101..112
FT /evidence="ECO:0000250"
FT DISULFID 126..140
FT /evidence="ECO:0000250"
FT MUTAGEN 338
FT /note="N->A: No effect on GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 339
FT /note="D->A: Slightly impaired GHR-mediated GH
FT internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 340
FT /note="D->A: Impaired GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 341
FT /note="S->A: Impaired GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 341
FT /note="S->L,T: Slightly impaired GHR-mediated GH
FT internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 342
FT /note="W->A: Impaired GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 342
FT /note="W->L: No effect on GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 343
FT /note="V->A: No effect on GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 343
FT /note="V->G: Impaired GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 344
FT /note="E->A: Impaired GHR-mediated GH internalization.
FT Greatly reduced ubiquitination."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 344
FT /note="E->D: No effect on GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 345
FT /note="F->A: Impaired GHR-mediated GH internalization.
FT Greatly reduced ubiquitination."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 345
FT /note="F->L,V: Impaired GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 345
FT /note="F->Y: No effect on GHR-mediated GH internalization.
FT No effect on ubiquitination."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 346
FT /note="I->A: Impaired GHR-mediated GH internalization.
FT Greatly reduced ubiquitination."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 346
FT /note="I->F: Slightly impaired GHR-mediated GH
FT internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 346
FT /note="I->L: No effect on GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 347
FT /note="E->A,D: Impaired GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 348
FT /note="L->A,V: Impaired GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 349
FT /note="D->A: Impaired GHR-mediated GH internalization.
FT Greatly reduced ubiquitination."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 349
FT /note="D->E: No effect on GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 349
FT /note="D->N: Impaired GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 350
FT /note="I->A: Impaired GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 351
FT /note="D->A: No effect on GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
FT MUTAGEN 352
FT /note="D->A: No effect on GHR-mediated GH internalization."
FT /evidence="ECO:0000269|PubMed:9878047"
SQ SEQUENCE 638 AA; 71077 MW; E05CCE1D7294624C CRC64;
MDLWQLLLTV ALAGSSDAFS GSEATPATLG RASESVQRVH PGLGTNSSGK PKFTKCRSPE
LETFSCHWTD GVHHGLKSPG SVQLFYIRRN TQEWTQEWKE CPDYVSAGEN SCYFNSSYTS
IWIPYCIKLT NNGGMVDQKC FSVEEIVQPD PPIGLNWTLL NVSLTGIHAD IQVRWEPPPN
ADVQKGWIVL EYELQYKEVN ETQWKMMDPV LSTSVPVYSL RLDKEYEVRV RSRQRSSEKY
GEFSEVLYVT LPQMSPFTCE EDFRFPWFLI IIFGIFGLTV MLFVFIFSKQ QRIKMLILPP
VPVPKIKGID PDLLKEGKLE EVNTILAIQD SYKPEFYNDD SWVEFIELDI DDPDEKTEGS
DTDRLLSNSH QKSLSVLAAK DDDSGRTSCY EPDILENDFN ASDGCDGNSE VAQPQRLKGE
ADLLCLDQKN QNNSPYHDVS PAAQQPEVVL AEEDKPRPLL TGEIESTLQA APSQLSNPNS
LANIDFYAQV SDITPAGSVV LSPGQKNKAG NSQCDAHPEV VSLCQTNFIM DNAYFCEADA
KKCIAVAPHV DVESRVEPSF NQEDIYITTE SLTTTAERSG TAEDAPGSEM PVPDYTSIHL
VQSPQGLVLN AATLPLPDKE FLSSCGYVST DQLNKILP
