Human Gene GHR (uc003jmt.3)
  Description: Homo sapiens growth hormone receptor (GHR), transcript variant 1, mRNA.
RefSeq Summary (NM_000163): This gene encodes a member of the type I cytokine receptor family, which is a transmembrane receptor for growth hormone. Binding of growth hormone to the receptor leads to receptor dimerization and the activation of an intra- and intercellular signal transduction pathway leading to growth. Mutations in this gene have been associated with Laron syndrome, also known as the growth hormone insensitivity syndrome (GHIS), a disorder characterized by short stature. In humans and rabbits, but not rodents, growth hormone binding protein (GHBP) is generated by proteolytic cleavage of the extracellular ligand-binding domain from the mature growth hormone receptor protein. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011].
Transcript (Including UTRs)
   Position: hg19 chr5:42,423,877-42,721,980 Size: 298,104 Total Exon Count: 10 Strand: +
Coding Region
   Position: hg19 chr5:42,565,977-42,719,526 Size: 153,550 Coding Exon Count: 9 

Page IndexSequence and LinksUniProtKB CommentsGenetic AssociationsMalaCardsCTD
Gene AllelesRNA-Seq ExpressionMicroarray ExpressionRNA StructureProtein StructureOther Species
GO AnnotationsmRNA DescriptionsPathwaysOther NamesModel InformationMethods
Data last updated at UCSC: 2013-06-14

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr5:42,423,877-42,721,980)mRNA (may differ from genome)Protein (638 aa)
Gene SorterGenome BrowserOther Species FASTAVisiGeneGene interactionsTable Schema
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neXtProtOMIMPubMedReactomeTreefamUniProtKB
Wikipedia

-  Comments and Description Text from UniProtKB
  ID: GHR_HUMAN
DESCRIPTION: RecName: Full=Growth hormone receptor; Short=GH receptor; AltName: Full=Somatotropin receptor; Contains: RecName: Full=Growth hormone-binding protein; Short=GH-binding protein; Short=GHBP; AltName: Full=Serum-binding protein; Flags: Precursor;
FUNCTION: Receptor for pituitary gland growth hormone involved in regulating postnatal body growth. On ligand binding, couples to the JAK2/STAT5 pathway (By similarity).
FUNCTION: The soluble form (GHBP) acts as a reservoir of growth hormone in plasma and may be a modulator/inhibitor of GH signaling.
FUNCTION: Isoform 2 up-regulates the production of GHBP and acts as a negative inhibitor of GH signaling.
SUBUNIT: On growth hormone (GH) binding, forms homodimers and binds JAK2 via a box 1-containing domain (By similarity). Binding to SOCS3 inhibits JAK2 activation, binding to CIS and SOCS2 inhibits STAT5 activation (By similarity). Interacts with ADAM17 (By similarity).
INTERACTION: Q16829:DUSP7; NbExp=2; IntAct=EBI-286316, EBI-1265847; P01241:GH1; NbExp=3; IntAct=EBI-286316, EBI-1026046; P16333:NCK1; NbExp=2; IntAct=EBI-286316, EBI-389883; Q9JLI4:Ncoa6 (xeno); NbExp=2; IntAct=EBI-286316, EBI-286271; P18031:PTPN1; NbExp=5; IntAct=EBI-286316, EBI-968788; P17706:PTPN2; NbExp=8; IntAct=EBI-286316, EBI-984930; P26045:PTPN3; NbExp=4; IntAct=EBI-286316, EBI-1047946; P43378:PTPN9; NbExp=2; IntAct=EBI-286316, EBI-742898; P23467:PTPRB; NbExp=3; IntAct=EBI-286316, EBI-1265766; Q9HD43:PTPRH; NbExp=4; IntAct=EBI-286316, EBI-1267176; Q12913:PTPRJ; NbExp=2; IntAct=EBI-286316, EBI-2264500;
SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein. Note=On growth hormone binding, GHR is ubiquitinated, internalized, down-regulated and transported into a degradative or non-degradative pathway (By similarity).
SUBCELLULAR LOCATION: Isoform 2: Cell membrane; Single-pass type I membrane protein. Note=Remains fixed to the cell membrane and is not internalized.
SUBCELLULAR LOCATION: Growth hormone-binding protein: Secreted. Note=Complexed to a substantial fraction of circulating GH (By similarity).
TISSUE SPECIFICITY: Expressed in various tissues with high expression in liver and skeletal muscle. Isoform 4 is predominantly expressed in kidney, bladder, adrenal gland and brain stem. Isoform 1 expression in placenta is predominant in chorion and decidua. Isoform 4 is highly expressed in placental villi. Isoform 2 is expressed in lung, stomach and muscle. Low levels in liver.
DOMAIN: The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell- surface receptor binding.
DOMAIN: The box 1 motif is required for JAK interaction and/or activation.
DOMAIN: The extracellular domain is the ligand-binding domain representing the growth hormone-binding protein (GHBP).
DOMAIN: The ubiquitination-dependent endocytosis motif (UbE) is required for recruitment of the ubiquitin conjugation system on to the receptor and for its internalization.
PTM: The soluble form (GHBP) is produced by phorbol ester-promoted proteolytic cleavage at the cell surface (shedding) by ADAM17/TACE. Shedding is inhibited by growth hormone (GH) binding to the receptor probably due to a conformational change in GHR rendering the receptor inaccessible to ADAM17 (By similarity).
PTM: On GH binding, phosphorylated on tyrosine residues in the cytoplasmic domain by JAK2 (By similarity).
PTM: On ligand binding, ubiquitinated on lysine residues in the cytoplasmic domain. This ubiquitination is not sufficient for GHR internalization (By similarity).
POLYMORPHISM: Genetic variation in GHR may act as phenotype modifier in familial hypercholesterolemia [MIM:143890] patients carrying a mutation in the LDLR gene.
DISEASE: Defects in GHR are a cause of Laron syndrome (LARS) [MIM:262500]. A severe form of growth hormone insensitivity characterized by growth impairment, short stature, dysfunctional growth hormone receptor, and failure to generate insulin-like growth factor I in response to growth hormone.
DISEASE: Defects in GHR may be a cause of idiopathic short stature autosomal (ISSA) [MIM:604271]. Short stature is defined by a subnormal rate of growth.
SIMILARITY: Belongs to the type I cytokine receptor family. Type 1 subfamily.
SIMILARITY: Contains 1 fibronectin type-III domain.
WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GHR";

-  Genetic Association Studies of Complex Diseases and Disorders
  Genetic Association Database (archive): GHR
CDC HuGE Published Literature: GHR
Positive Disease Associations: Acromegaly , blood pressure, arterial hypertension , cholesterol height , diabetes, type 2 metabolism syndrome , grow intrauterine growth , growth hormone concentrations insulin-like growth factor , growth hormone responsiveness , growth response to growth hormone therapy , mandibular height , serum markers of iron status , small-for-gestational-age , systemic lupus erythematosus , Transferrin
Related Studies:
  1. Acromegaly
    Ignacio Bernabeu , et al. The Journal of clinical endocrinology and metabolism 2010 95(1):222-9, The exon 3-deleted growth hormone receptor is associated with better response to pegvisomant therapy in acromegaly., The Journal of clinical endocrinology and metabolism 2010 95(1):222-9. [PubMed 19850678]
    The exon 3 deletion in the GHR predicts an improved response to pegvisomant therapy in acromegaly.
  2. blood pressure, arterial hypertension
    Kokubo, Y. et al. 2006, Association of sixty-one non-synonymous polymorphisms in forty-one hypertension candidate genes with blood pressure variation and hypertension, Hypertens Res 2006 29(8) 611-9. [PubMed 17137217]
  3. cholesterol height
    Ihara, K. et al. 2007, The Leu544Ile polymorphism of the growth hormone receptor gene affects the serum cholesterol levels during GH treatment in children with GH deficiency, Clin Endocrinol (Oxf) 2007. [PubMed 17547682]
    The Leu544Ile polymorphism of the GHR gene is associated with cholesterol levels in boys with GH deficiency.
           more ... click here to view the complete list

-  MalaCards Disease Associations
  MalaCards Gene Search: GHR
Diseases sorted by gene-association score: laron dwarfism* (1714), growth hormone insensitivity, partial* (1680), hypercholesterolemia, familial* (332), growth hormone deficiency, isolated partial* (283), turner syndrome (14), growth retardation with deafness and mental retardation due to igf1 deficiency (14), acromegaly (13), insulin-like growth factor i (13), functioning pituitary adenoma (12), isolated growth hormone deficiency (10), dwarfism (10), acromesomelic dysplasia, maroteaux type (9), uremia (8), non-functioning pituitary adenoma (8), anorexia nervosa (8), localized osteosarcoma (7), acromesomelic dysplasia (6), intracranial hypertension, idiopathic (6), hyperpituitarism (6), growth hormone deficiency, isolated, type ib (5), pituitary hormone deficiency, combined, 2 (5), growth hormone deficiency, isolated, type ii (5), noonan syndrome 1 (4), pituitary-dependent cushing's disease (3), diabetes mellitus, insulin-dependent (2), obesity (1)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

+  Common Gene Haplotype Alleles
  Press "+" in the title bar above to open this section.

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 26.55 RPKM in Adipose - Subcutaneous
Total median expression: 185.60 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -116.40192-0.606 Picture PostScript Text
3' UTR -605.102454-0.247 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR003961 - Fibronectin_type3
IPR025871 - GHBP
IPR015152 - Growth/epo_recpt_lig-bind
IPR013783 - Ig-like_fold
IPR003528 - Long_hematopoietin_rcpt_CS

Pfam Domains:
PF00041 - Fibronectin type III domain
PF09067 - Erythropoietin receptor, ligand binding
PF12772 - Growth hormone receptor binding

SCOP Domains:
49265 - Fibronectin type III

Protein Data Bank (PDB) 3-D Structure
MuPIT help
1A22 - X-ray MuPIT 1AXI - X-ray MuPIT 1HWG - X-ray MuPIT 1HWH - X-ray MuPIT 1KF9 - X-ray MuPIT 2AEW - X-ray MuPIT 3HHR - X-ray MuPIT


ModBase Predicted Comparative 3D Structure on P10912
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The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
No orthologNo orthologNo orthologNo orthologNo orthologNo ortholog
      
      
      
      
      

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0004896 cytokine receptor activity
GO:0005515 protein binding
GO:0017046 peptide hormone binding
GO:0019838 growth factor binding
GO:0019901 protein kinase binding
GO:0042802 identical protein binding
GO:0042803 protein homodimerization activity
GO:0070064 proline-rich region binding

Biological Process:
GO:0000187 activation of MAPK activity
GO:0000255 allantoin metabolic process
GO:0006101 citrate metabolic process
GO:0006103 2-oxoglutarate metabolic process
GO:0006105 succinate metabolic process
GO:0006107 oxaloacetate metabolic process
GO:0006549 isoleucine metabolic process
GO:0006573 valine metabolic process
GO:0006600 creatine metabolic process
GO:0006631 fatty acid metabolic process
GO:0006897 endocytosis
GO:0007259 JAK-STAT cascade
GO:0019221 cytokine-mediated signaling pathway
GO:0019530 taurine metabolic process
GO:0031623 receptor internalization
GO:0032355 response to estradiol
GO:0032870 cellular response to hormone stimulus
GO:0040014 regulation of multicellular organism growth
GO:0040018 positive regulation of multicellular organism growth
GO:0042445 hormone metabolic process
GO:0042531 positive regulation of tyrosine phosphorylation of STAT protein
GO:0042976 activation of Janus kinase activity
GO:0046449 creatinine metabolic process
GO:0046898 response to cycloheximide
GO:0048009 insulin-like growth factor receptor signaling pathway
GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation
GO:0060396 growth hormone receptor signaling pathway
GO:0060397 JAK-STAT cascade involved in growth hormone signaling pathway

Cellular Component:
GO:0005576 extracellular region
GO:0005615 extracellular space
GO:0005829 cytosol
GO:0005886 plasma membrane
GO:0005887 integral component of plasma membrane
GO:0009986 cell surface
GO:0016020 membrane
GO:0016021 integral component of membrane
GO:0036464 cytoplasmic ribonucleoprotein granule
GO:0043235 receptor complex
GO:0070195 growth hormone receptor complex


-  Descriptions from all associated GenBank mRNAs
  X06562 - Human mRNA for growth hormone receptor.
BC136496 - Homo sapiens growth hormone receptor, mRNA (cDNA clone MGC:168108 IMAGE:9020485), complete cds.
S97393 - growth hormone receptor {5' region} [human, placenta, mRNA Partial, 455 nt].
Z11801 - H.sapiens mRNA for growth hormone receptor 5'-untranslated region V2.
Z11850 - H.sapiens mRNA for somatotropin receptor 5' upstream region.
JD537537 - Sequence 518561 from Patent EP1572962.
JD457909 - Sequence 438933 from Patent EP1572962.
JD304828 - Sequence 285852 from Patent EP1572962.
JD156256 - Sequence 137280 from Patent EP1572962.
JD097526 - Sequence 78550 from Patent EP1572962.
JD223980 - Sequence 205004 from Patent EP1572962.
JD316575 - Sequence 297599 from Patent EP1572962.
JD437939 - Sequence 418963 from Patent EP1572962.
JD360855 - Sequence 341879 from Patent EP1572962.
JD309412 - Sequence 290436 from Patent EP1572962.
JD309872 - Sequence 290896 from Patent EP1572962.
JD235126 - Sequence 216150 from Patent EP1572962.
JD235127 - Sequence 216151 from Patent EP1572962.
JD140623 - Sequence 121647 from Patent EP1572962.
JD198433 - Sequence 179457 from Patent EP1572962.
JD153212 - Sequence 134236 from Patent EP1572962.
JD527692 - Sequence 508716 from Patent EP1572962.
JD161508 - Sequence 142532 from Patent EP1572962.
JD547578 - Sequence 528602 from Patent EP1572962.
JD542037 - Sequence 523061 from Patent EP1572962.
JD086948 - Sequence 67972 from Patent EP1572962.
JD261734 - Sequence 242758 from Patent EP1572962.
JD430785 - Sequence 411809 from Patent EP1572962.
JD558070 - Sequence 539094 from Patent EP1572962.
JD265194 - Sequence 246218 from Patent EP1572962.
JD174012 - Sequence 155036 from Patent EP1572962.
JD324289 - Sequence 305313 from Patent EP1572962.
JD318620 - Sequence 299644 from Patent EP1572962.
JD374583 - Sequence 355607 from Patent EP1572962.
JD489367 - Sequence 470391 from Patent EP1572962.
JD071951 - Sequence 52975 from Patent EP1572962.
JD322886 - Sequence 303910 from Patent EP1572962.
JD203745 - Sequence 184769 from Patent EP1572962.
JD058784 - Sequence 39808 from Patent EP1572962.
JD505163 - Sequence 486187 from Patent EP1572962.
JD285431 - Sequence 266455 from Patent EP1572962.
JD505164 - Sequence 486188 from Patent EP1572962.
JD505165 - Sequence 486189 from Patent EP1572962.
JD301086 - Sequence 282110 from Patent EP1572962.
JD312107 - Sequence 293131 from Patent EP1572962.
JD312108 - Sequence 293132 from Patent EP1572962.
JD346588 - Sequence 327612 from Patent EP1572962.
JD346589 - Sequence 327613 from Patent EP1572962.
JD506242 - Sequence 487266 from Patent EP1572962.
JD091593 - Sequence 72617 from Patent EP1572962.
JD302277 - Sequence 283301 from Patent EP1572962.
JD261174 - Sequence 242198 from Patent EP1572962.
JD200620 - Sequence 181644 from Patent EP1572962.
JD240704 - Sequence 221728 from Patent EP1572962.
JD545473 - Sequence 526497 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04060 - Cytokine-cytokine receptor interaction
hsa04080 - Neuroactive ligand-receptor interaction
hsa04630 - Jak-STAT signaling pathway

BioCarta from NCI Cancer Genome Anatomy Project
h_longevityPathway - The IGF-1 Receptor and Longevity
h_tffPathway - Trefoil Factors Initiate Mucosal Healing
h_eif4Pathway - Regulation of eIF4e and p70 S6 Kinase
h_aktPathway - AKT Signaling Pathway
h_ghPathway - Growth Hormone Signaling Pathway

Reactome (by CSHL, EBI, and GO)

Protein P10912 (Reactome details) participates in the following event(s):

R-HSA-982792 Growth hormone receptor binds JAK2
R-HSA-1168777 Metalloprotease cleavage of GHR
R-HSA-1362465 GHBP binds GHR
R-HSA-1362485 GHBP binds GH
R-HSA-982775 Growth hormone receptor dimerizes
R-HSA-982778 Growth hormone binds the growth hormone receptor
R-HSA-1168456 Growth hormone receptor binds Lyn
R-HSA-982807 JAK2 phosphorylation of GHR
R-HSA-1168768 JAK2 binds STAT1/3
R-HSA-1168393 STAT5 association with GHR
R-HSA-1168445 PTP1B binds the GH receptor complex
R-HSA-1168809 SOCS binding to GHR
R-HSA-1168813 SOCS binding to JAK2
R-HSA-1168839 SHP1 (PTPN6) binds JAK2 in the receptor complex
R-HSA-1168894 p-STAT5A/B dissociates from the Growth Hormone receptor
R-HSA-1168767 JAK2 phosphorylates STAT1/STAT3
R-HSA-1168423 JAK2 phosphorylation of IRS-1/2
R-HSA-1168394 STAT5 tyrosine phosphorylation
R-HSA-1169192 PTP1B dephosphorylates GHR
R-HSA-1169210 PTP1B dephosphorylates JAK2
R-HSA-1169188 SHP1 (PTPN6) dephosphorylates JAK2
R-HSA-982772 Growth hormone receptor signaling
R-HSA-1280215 Cytokine Signaling in Immune system
R-HSA-168256 Immune System
R-HSA-1170546 Prolactin receptor signaling

-  Other Names for This Gene
  Alternate Gene Symbols: GHR_HUMAN, NM_000163, NP_001229335, P10912, Q9HCX2
UCSC ID: uc003jmt.3
RefSeq Accession: NM_000163
Protein: P10912 (aka GHR_HUMAN)
CCDS: CCDS3940.1, CCDS56364.1

-  Gene Model Information
 
category: coding nonsense-mediated-decay: no RNA accession: NM_000163.4
exon count: 10CDS single in 3' UTR: no RNA size: 4563
ORF size: 1917CDS single in intron: no Alignment % ID: 100.00
txCdsPredict score: 4034.00frame shift in genome: no % Coverage: 100.00
has start codon: yes stop codon in genome: no # of Alignments: 1
has end codon: yes retained intron: no # AT/AC introns 0
selenocysteine: no end bleed into intron: 0# strange splices: 0
Click here for a detailed description of the fields of the table above.

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.