Evolution of the Growth Hormone Receptor Family


The growth hormone receptor (GHR) family includes receptors for growth hormone and prolactin receptor (PRLR). GHRs and PRLRs are membrane receptors that possess several evolutionarily conserved features: a hormone‐binding extracellular domain, a single‐chain transmembrane domain and an intracellular domain important for activating intracellular signal systems that mediate cell‐specific responses. PRLRs diverged early from a common GHR/PRLR in jawless fish (e.g. Agnathans), followed by subsequent divergence of GHRs in the Actinopterygian lineage that gave rise to teleosts and in the Sarcopterygian lineage that gave rise to tetrapods. Structural heterogeneity of GHRs in teleosts results from the existence of multiple genes that arose through a series of independent gene duplication events during the course of their evolution and from alternative transcripts of a single gene. Differential receptor–ligand interactions, differential receptor–cell signalling system interactions and the differential expression of alternate GHR forms underlie the vast array of functions elicited by GH.

Key Concepts

  • Growth hormone regulates many processes, including growth, metabolism, osmoregulation, reproduction and behaviour.
  • Growth hormone receptors are single‐pass membrane‐bound receptors that mediate the actions of growth hormone.
  • The growth hormone receptor family arose through a series of gene duplication events during the course of vertebrate evolution.
  • The multiple actions of growth hormone arise from binding to variant forms of growth hormone receptor and from activation of alternate cell signalling pathways.

Keywords: growth hormone; growth hormone receptor; molecular evolution; gene duplication; functional divergence of duplicated genes

Figure 1. Diagrammatic representation of the growth hormone receptor (GHR). GHR is a member of the class I cytokine receptor family and possesses three main domains: an extracellular domain, a transmembrane domain and an intracellular domain. The extracellular segment can be divided into two structural regions, domain 1 and domain 2, which are important for ligand binding and receptor dimerisation, respectively. A single transmembrane domain traverses the cell membrane. The intracellular domain contains two well recognised and conserved domains, Box 1 and Box 2, which appear to be responsible for signal transduction and receptor internalisation, respectively.
Figure 2. Three‐dimensional models of the extracellular domains of the growth hormone receptor (GHR)/prolactin receptor (PRLR) from sea lamprey (centre) and the GHRs and PRLR from rainbow trout. The homology models were based on deduced protein sequences using the SWISS‐MODEL workspace (Bordoli and Schwede, ) to produce coordinates based on templates; GHR models used the crystal structure of human GH‐GHR2 (PBD ID: 3hhr) as template and the PRL model used the crystal structure of human PRL‐PRLR2 (PDB IDid: 3ew3) as template; images were generated with POLYVIEW‐3D (Porollo and Meller, ). Reproduced from Ellens et al. (2013) © Elsevier.
Figure 3. Phylogenetic tree of the known growth hormone receptors (GHRs) of fish and selected other vertebrates. Prolactin receptors (PRLRs) from selected teleosts are included for comparison. The tree was based on the alignment of amino acid sequences using the N–J bootstrap method in Clustal X and considered only completely overlapping segments >300 nt in length. The tree was rooted using the erythropoietin receptor as an out group and was visualised with TreeView. The branch lengths represent amino acid substitutions per site from a common ancestor and are proportional to the estimated time since divergence occurred. The nomenclature for a particular receptor reflects that given by the authors originally or that which appears in databases; if the sequence was not annotated or the receptor type/subtype was not specified, the designation on the tree is ours and was chosen for consistency with the phylogenetic analysis and our proposed nomenclature. We recommend abandonment of the term somatolactin receptor (SLR), and the use of letters to designate GHR subtypes in teleosts. Sequences were obtained from either GenBank (accession numbers in parentheses) or Ensembl (protein ID numbers in parentheses) as follows: Atlantic halibut GHR (DQ062814), Atlantic salmon GHR1 (NM001123576), Atlantic salmon GHR2 (NM001123594), Atlantic salmon SLR (NM001141617), black seabream GHR1 (AF502071), black seabream GHR2 (AY662334), Catla GHR (AY691178), Channel catfish GHR (DQ103502), chicken GHR (NM_001001293), Chilean flounder GHR1 (EU004149), Coelacanth GHR (ENSLACG00000005546), coho salmon GHR1 (AF403539), coho salmon GHR2 (AF403540), common carp GHR (AY741100), common carp PRLR (AY044448), frog GHR (AF193799), gilthead seabream GHR1 (AF438176), gilthead seabream GHR2 (AY573601), goldfish GHR (AF293417), goldfish PRLR (AF144012), grass carp GHR (AY283778), Japanese crucian carp GHR (ADZ13485), Japanese eel GHR1 (AB180476), Japanese eel GHR2 (AB180477), Japanese flounder GHR (AB058418), Japanese medaka GHR (NM_001122905), Japanese medaka SLR (NP_001098560), jian carp GHR1a (ADC35573), jian carp GHR1b (ADC35574), jian carp GHR2a (ADC35576), jian carp GHR2b (ADC35577), lamprey GHR/PRLR (this sequence), lungfish GHR (EF158850), masu salmon GHR (AB071216), masu salmon SLR (AB121047), Mozambique tilapia GHR1(AB115179), Mozambique tilapia GHR2 (EF452496), Mozambique tilapia PRLR (EU999785), Mrigal carp GHR (AY691179), Nile tilapia GHR1 (AY973232), Nile tilapia GHR2 (AY973233), Nile tilapia PRLR(L34783), opossum GHR (NM001032976), orange spotted grouper GHR1 (EF052273), orange spotted grouper GHR2 (EF052274), orangefin labeo GHR (EU147276), pigeon GHR (D84308), rainbow trout GHR1 (JQ408978), rainbow trout GHR2a (NM001124535), rainbow trout GHR2b (NM001124731), rainbow trout PRLR (AF229197), rat erythropoietin receptor (AAH89810), rat GHR GHR (NM017094), rohu labeo GHR (AY691177), South American cichlid SLR (FJ208943), southern catfish GHR1 (AY336104), southern catfish GHR2 (AY973231), stickleback GHR (ENSGACT00000023732), sturgeon GHR (EF158851), Takifugu GHR1 (BAK86396), Takifugu GHR2 (BAK86397), Tetraodon GHR (ENSTNIP00000004152), tongue sole GHR1 (FJ608664), turbot GHR (AF352396), turtle GHR (AF211173), wami tilapia GHR1 (EF371466), wami tilapia GHR2 (EF371467), Wuchang bream GHRa (AFC38427), Wuchang bream GHRb (AFC38428), yellowfin seabream GHR2 (AEW29012), zebrafish GHRa (EU649774) and zebrafish GHRb (EU649775). Reproduced from Ellens et al. (2013) © Elsevier.
Figure 4. Synteny maps of growth hormone receptor (GHR) loci and the genes flanking them in humans and fish. Horizontal lines represent partial chromosomes/scaffolds/groups/contigs with species name listed on the left and the chromosome/scaffold/group/contig number and size listed on the right for each line; gene positions are relative and are omitted for clarity; The 5′–3′ orientation of each gene, when known, is indicated by >. Coloured boxes on the lines represent genes that were manually annotated as follows: GHRs and teleost type 1 GHRs (yellow), teleost type‐2 GHRs (dark green), C5orf28 (cyan), C6 (blue), C7 (red) CCDC152 (pink), PIP5K1B (green horizontal strip), TJP2 (red vertical strip), IP011 (green diagonal strip), OXCT (red vertical strip), PLCXD3 (purple), C5orf51 (orange), FBX04 (dark blue) SEPP1 (bright green) and ZNF131 (teal). Reproduced from Ellens et al. (2013) © Elsevier.
Figure 5. Proposed evolution of the growth hormone receptor (GHR) family in vertebrates. The divergence of GHRs and prolactin receptors (PRLRs) results from a series of gene duplication events over the course of vertebrate evolution. Subsequent duplication events in teleosts results in multiple types and subtypes of GHRs in this lineage. Reproduced from Ellens et al. (2013) © Elsevier.


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Further Reading

Brooks AJ and Waters MJ (2010) The growth hormone receptor: mechanism of activation and clinical implications. Nature Reviews Endocrinology 6: 515–525.

Ellens ER and Sheridan MA (2013) Molecular evolution and regulation of growth hormone signaling: toward a highly integrated control system of growth. In: Polakof S and Moon TP (eds) Trout: From Physiology to Conservation, pp. 269–306. New York: Nova Publishers.

Ellens ER, Kittilson JD, Hall JA, Sower SA and Sheridan MA (2013) Evolutionary origin and divergence of the growth hormone receptor family: Insight from studies on sea lamprey. General and Comparative Endocrinology 192: 222–236.

Fukamachi S and Meyer A (2007) Evolution of receptors for growth hormone and somatolactin in fish and land vertebrates: Lessons from the lungfish and sturgeon orthologues. Journal of Molecular Evolution 65: 359–372.

Liongue C and Ward A (2007) Evolution of class I cytokine receptors. BMC Evolutionary Biology 7: 120–123.

Ohno S (1970) Evolution by Gene Duplication. New York: Springer‐Verlag.

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Sheridan, Mark A(Apr 2016) Evolution of the Growth Hormone Receptor Family. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026413]