GHR_RAT
ID GHR_RAT Reviewed; 638 AA.
AC P16310; Q64236; Q80XW9;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1990, sequence version 1.
DT 03-AUG-2022, entry version 180.
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 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].
RC TISSUE=Liver;
RX PubMed=2722883; DOI=10.1016/s0021-9258(18)81745-8;
RA Mathews L.S., Enberg B., Norstedt G.;
RT "Regulation of rat growth hormone receptor gene expression.";
RL J. Biol. Chem. 264:9905-9910(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE (ISOFORMS 1 AND 2).
RX PubMed=2792761; DOI=10.1101/gad.3.8.1199;
RA Baumbach W.R., Horner D.L., Logan J.S.;
RT "The growth hormone-binding protein in rat serum is an alternatively
RT spliced form of the rat growth hormone receptor.";
RL Genes Dev. 3:1199-1205(1989).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Adipose tissue;
RX PubMed=1446642; DOI=10.1210/endo.131.6.1446642;
RA Frick G.P., Goodman H.M.;
RT "Characterization of the short isoform of the growth hormone receptor
RT synthesized by rat adipocytes.";
RL Endocrinology 131:3083-3090(1992).
RN [4]
RP PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 2).
RX PubMed=8921876; DOI=10.1016/0378-1119(96)00277-6;
RA Zhou Y., He L., Kopchick J.J.;
RT "Structural comparison of a portion of the rat and mouse growth hormone
RT receptor/binding protein genes.";
RL Gene 177:257-259(1996).
RN [5]
RP DOMAIN JAK2 BINDING.
RX PubMed=8063815; DOI=10.1016/s0021-9258(17)31863-x;
RA VanderKuur J.A., Wang X., Zhang L., Campbell G.S., Allevato G.,
RA Billestrup N., Norstedt G., Carter-Su C.;
RT "Domains of the growth hormone receptor required for association and
RT activation of JAK2 tyrosine kinase.";
RL J. Biol. Chem. 269:21709-21717(1994).
RN [6]
RP ENDOCYTOSIS SIGNAL, AND MUTAGENESIS OF PHE-346.
RX PubMed=7615519; DOI=10.1074/jbc.270.29.17210;
RA Allevato G., Billestrup N., Goujon L., Galsgaard E.D., Norstedt G.,
RA Postel-Vinay M.-C., Kelly P.A., Nielsen J.H.;
RT "Identification of phenylalanine 346 in the rat growth hormone receptor as
RT being critical for ligand-mediated internalization and down-regulation.";
RL J. Biol. Chem. 270:17210-17214(1995).
RN [7]
RP INTERACTION WITH SOCS FAMILY PROTEINS.
RX PubMed=10585430; DOI=10.1074/jbc.274.50.35553;
RA Ram P.A., Waxman D.J.;
RT "SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling
RT by multiple mechanisms.";
RL J. Biol. Chem. 274:35553-35561(1999).
RN [8]
RP PHOSPHORYLATION BY JAK2.
RX PubMed=7545168; DOI=10.1074/jbc.270.37.21738;
RA VanderKuur J.A., Wang X., Zhang L., Allevato G., Billestrup N.,
RA Carter-Su C.;
RT "Growth hormone-dependent phosphorylation of tyrosine 333 and/or 338 of the
RT growth hormone receptor.";
RL J. Biol. Chem. 270:21738-21744(1995).
RN [9]
RP PHOSPHORYLATION, AND STAT5 ACTIVATION.
RX PubMed=9231797; DOI=10.1210/endo.138.8.5332;
RA Smit L.S., Vanderkuur J.A., Stimage A., Han Y., Luo G., Yu-Lee L.-Y.,
RA Schwartz J., Carter-Su C.;
RT "Growth hormone-induced tyrosyl phosphorylation and deoxyribonucleic acid
RT binding activity of Stat5A and Stat5B.";
RL Endocrinology 138:3426-3434(1997).
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.
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. Binding to SOCS3 inhibits JAK2
CC activation, binding to CIS and SOCS2 inhibits STAT5 activation.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Note=On growth hormone binding, GHR is ubiquitinated,
CC internalized, down-regulated and transported into a degradative or non-
CC degradative pathway.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Secreted. Membrane. Note=Mainly
CC secreted. In adipose tissue, isoform 2 is mostly membrane associated.
CC -!- SUBCELLULAR LOCATION: [Growth hormone-binding protein]: Secreted
CC {ECO:0000250}. Note=Complexed to a substantial fraction of circulating
CC GH. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P16310-1; Sequence=Displayed;
CC Name=2; Synonyms=Short from, GHBP;
CC IsoId=P16310-2; Sequence=VSP_010231, VSP_010232;
CC -!- TISSUE SPECIFICITY: Highest expression in liver. Also expressed in
CC heart, kidney and muscle.
CC -!- DEVELOPMENTAL STAGE: Expression is low at birth. Increases to adult
CC levels after 5 weeks.
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. {ECO:0000269|PubMed:8063815}.
CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or
CC activation. {ECO:0000269|PubMed:8063815}.
CC -!- DOMAIN: The extracellular domain is the ligand-binding domain
CC representing the growth hormone-binding protein (GHBP).
CC {ECO:0000269|PubMed:8063815}.
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. {ECO:0000269|PubMed:8063815}.
CC -!- PTM: On GH binding, phosphorylated on tyrosine residues in the
CC cytoplasmic domain by JAK2. Phosphorylation on either (or all of) Tyr-
CC 534, Tyr-566 and/or Tyr-627 is required for STAT5 activation.
CC Phosphorylation on Tyr-333 would seem necessary for JAK2 activation.
CC {ECO:0000269|PubMed:7545168, ECO:0000269|PubMed:9231797}.
CC -!- PTM: On ligand binding, ubiquitinated on lysine residues in the
CC cytoplasmic domain. This ubiquitination is not sufficient for GHR
CC internalization (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 1
CC subfamily. {ECO:0000305}.
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DR EMBL; J04811; AAA41219.1; -; mRNA.
DR EMBL; S49003; AAP13886.1; -; mRNA.
DR EMBL; U44722; AAC52916.1; -; Genomic_DNA.
DR PIR; A32985; A33505.
DR PIR; B32985; B32985.
DR RefSeq; NP_058790.1; NM_017094.1. [P16310-1]
DR RefSeq; XP_008758976.1; XM_008760754.1. [P16310-1]
DR AlphaFoldDB; P16310; -.
DR SMR; P16310; -.
DR BioGRID; 247275; 1.
DR DIP; DIP-63N; -.
DR IntAct; P16310; 3.
DR MINT; P16310; -.
DR STRING; 10116.ENSRNOP00000044119; -.
DR GlyGen; P16310; 4 sites.
DR iPTMnet; P16310; -.
DR PhosphoSitePlus; P16310; -.
DR PaxDb; P16310; -.
DR PRIDE; P16310; -.
DR Ensembl; ENSRNOT00000021081; ENSRNOP00000021081; ENSRNOG00000015654. [P16310-2]
DR Ensembl; ENSRNOT00000046951; ENSRNOP00000044119; ENSRNOG00000015654. [P16310-1]
DR GeneID; 25235; -.
DR KEGG; rno:25235; -.
DR CTD; 2690; -.
DR RGD; 2687; Ghr.
DR eggNOG; KOG3555; Eukaryota.
DR GeneTree; ENSGT00940000159987; -.
DR HOGENOM; CLU_022322_0_0_1; -.
DR InParanoid; P16310; -.
DR OMA; YCIKLTN; -.
DR OrthoDB; 346239at2759; -.
DR PhylomeDB; P16310; -.
DR Reactome; R-RNO-1170546; Prolactin receptor signaling.
DR Reactome; R-RNO-982772; Growth hormone receptor signaling.
DR PRO; PR:P16310; -.
DR Proteomes; UP000002494; Chromosome 2.
DR Bgee; ENSRNOG00000015654; Expressed in liver and 18 other tissues.
DR ExpressionAtlas; P16310; baseline and differential.
DR Genevisible; P16310; RN.
DR GO; GO:0009986; C:cell surface; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0036464; C:cytoplasmic ribonucleoprotein granule; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR GO; GO:0005615; C:extracellular space; IDA:RGD.
DR GO; GO:0019898; C:extrinsic component of membrane; ISO:RGD.
DR GO; GO:0070195; C:growth hormone receptor complex; ISO:RGD.
DR GO; GO:0016021; C:integral component of membrane; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; ISO:RGD.
DR GO; GO:0005739; C:mitochondrion; IDA:RGD.
DR GO; GO:0043025; C:neuronal cell body; IDA:RGD.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0043235; C:receptor complex; ISO:RGD.
DR GO; GO:0019955; F:cytokine binding; IBA:GO_Central.
DR GO; GO:0004896; F:cytokine receptor activity; IBA:GO_Central.
DR GO; GO:0019838; F:growth factor binding; ISO:RGD.
DR GO; GO:0004903; F:growth hormone receptor activity; IDA:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0017046; F:peptide hormone binding; ISO:RGD.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0019901; F:protein kinase binding; IDA:BHF-UCL.
DR GO; GO:0019903; F:protein phosphatase binding; IMP:RGD.
DR GO; GO:0042169; F:SH2 domain binding; IDA:RGD.
DR GO; GO:0042976; P:activation of Janus kinase activity; IDA:RGD.
DR GO; GO:0060351; P:cartilage development involved in endochondral bone morphogenesis; IEP:RGD.
DR GO; GO:0032870; P:cellular response to hormone stimulus; ISO:RGD.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IEP:RGD.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IBA:GO_Central.
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:0042445; P:hormone metabolic process; ISO:RGD.
DR GO; GO:0009755; P:hormone-mediated signaling pathway; IDA:RGD.
DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; ISO:RGD.
DR GO; GO:1901215; P:negative regulation of neuron death; IMP:RGD.
DR GO; GO:0045597; P:positive regulation of cell differentiation; IEP:RGD.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:BHF-UCL.
DR GO; GO:0040018; P:positive regulation of multicellular organism growth; ISO:RGD.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISO:RGD.
DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; IDA:RGD.
DR GO; GO:0007259; P:receptor signaling pathway via JAK-STAT; IDA:BHF-UCL.
DR GO; GO:0040014; P:regulation of multicellular organism growth; ISO:RGD.
DR GO; GO:0034097; P:response to cytokine; IEP:RGD.
DR GO; GO:0032094; P:response to food; IEP:RGD.
DR GO; GO:0051384; P:response to glucocorticoid; IEP:RGD.
DR GO; GO:0009629; P:response to gravity; IEP:RGD.
DR GO; GO:0060416; P:response to growth hormone; IEP:RGD.
DR GO; GO:0009725; P:response to hormone; IEP:RGD.
DR GO; GO:0070555; P:response to interleukin-1; IEP:RGD.
DR GO; GO:0043278; P:response to morphine; IEP:RGD.
DR GO; GO:0043434; P:response to peptide hormone; IEP:RGD.
DR GO; GO:0019530; P:taurine metabolic process; ISO:RGD.
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; PF12772; GHBP; 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 Alternative splicing; Cell membrane; Disulfide bond; Endocytosis;
KW Glycoprotein; Membrane; Phosphoprotein; Receptor; Reference proteome;
KW Secreted; Signal; Transmembrane; Transmembrane helix; Ubl conjugation.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..638
FT /note="Growth hormone receptor"
FT /id="PRO_0000010969"
FT CHAIN 19..256
FT /note="Growth hormone-binding protein"
FT /evidence="ECO:0000250"
FT /id="PRO_0000010970"
FT TOPO_DOM 19..265
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 266..289
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 290..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 295..380
FT /note="Required for JAK2 binding"
FT REGION 357..389
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 240..244
FT /note="WSXWS motif"
FT MOTIF 298..306
FT /note="Box 1 motif"
FT MOTIF 341..350
FT /note="UbE motif"
FT COMPBIAS 360..389
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 346
FT /note="Required for endocytosis and down-regulation"
FT MOD_RES 342
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P10912"
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 VAR_SEQ 263..279
FT /note="DFRFPWFLIIIFGIFGV -> GPKFNSQHPHQEIDNHL (in isoform
FT 2)"
FT /evidence="ECO:0000303|PubMed:1446642"
FT /id="VSP_010231"
FT VAR_SEQ 280..638
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:1446642"
FT /id="VSP_010232"
FT MUTAGEN 346
FT /note="F->A: No internalization nor down-regulation. No
FT effect on transcriptional signaling."
FT /evidence="ECO:0000269|PubMed:7615519"
SQ SEQUENCE 638 AA; 71237 MW; 0D8E9AF759A21A3B CRC64;
MDLWRVFLTL ALAVSSDMFP GSGATPATLG KASPVLQRIN PSLRESSSGK PRFTKCRSPE
LETFSCYWTE GDDHNLKVPG SIQLYYARRI AHEWTPEWKE CPDYVSAGAN SCYFNSSYTS
IWIPYCIKLT TNGDLLDEKC FTVDEIVQPD PPIGLNWTLL NISLPGIRGD IQVSWQPPPS
ADVLKGWIIL EYEIQYKEVN ETKWKTMSPI WSTSVPLYSL RLDKEHEVRV RSRQRSFEKY
SEFSEVLRVT FPQMDTLAAC EEDFRFPWFL IIIFGIFGVA VMLFVVIFSK QQRIKMLILP
PVPVPKIKGI DPDLLKEGKL EEVNTILGIH DNYKPDFYND DSWVEFIELD IDDADEKTEE
SDTDRLLSDD QEKSAGILGA KDDDSGRTSC YDPDILDTDF HTSDMCDGTS EFAQPQKLKA
EADLLCLDQK NLKNSPYDAS LGSLHPSITL TMEDKPQPLL GSETESTHQL PSTPMSSPVS
LANIDFYAQV SDITPAGGVV LSPGQKIKAG LAQGNTQLEV AAPCQENYSM NSAYFCESDA
KKCIAAAPHM EATTCVKPSF NQEDIYITTE SLTTTARMSE TADTAPDAEP VPDYTTVHTV
KSPRGLILNA TALPLPDKKK FLSSCGYVST DQLNKIMQ
