rEvIEWS

The growth hormone receptor: mechanism

of activation and clinical implications
Andrew J. Brooks and Michael J. Waters
Abstract | Growth hormone is widely used clinically to promote growth and anabolism and for other purposes. Its
actions are mediated via the growth hormone receptor, both directly by tyrosine kinase activation and indirectly by
induction of insulin-like growth factor 1 (IGF-1). Insensitivity to growth hormone (Laron syndrome) can result from
mutations in the growth hormone receptor and can be treated with IGF-1. This treatment is, however, not fully
effective owing to the loss of the direct actions of growth hormone and altered availability of exogenous IGF-1.
Excessive activation of the growth hormone receptor by circulating growth hormone results in gigantism
and acromegaly, whereas cell transformation and cancer can occur in response to autocrine activation of
the receptor. Advances in understanding the mechanism of receptor activation have led to a model in which the
growth hormone receptor exists as a constitutive dimer. Binding of the hormone realigns the subunits by rotation
and closer apposition, resulting in juxtaposition of the catalytic domains of the associated tyrosine-protein
kinase JAK2 below the cell membrane. This change results in activation of JAK2 by transphosphorylation, then
phosphorylation of receptor tyrosines in the cytoplasmic domain, which enables binding of adaptor proteins, as
well as direct phosphorylation of target proteins. This model is discussed in the light of salient information from
closely related class 1 cytokine receptors, such as the erythropoietin, prolactin and thrombopoietin receptors.
Brooks, A. J. & Waters, M. J. Nat. Rev. Endocrinol. 6, 515–525 (2010); published online 27 July 2010; doi:10.1038/nrendo.2010.123

Introduction
Growth hormone, also called somatotropin, is a peptide been gained from both animal models and human cases
hormone produced in the anterior pituitary gland that of growth hormone excess, for example, the giant mouse,
promotes cell division, regeneration and growth. Growth which expresses a bovine growth hormone transgene,
hormone mediates its pleiotropic effects through the and human growth hormone excess syndromes, such as
growth hormone receptor, both directly, via activation gigantism in children or acromegaly in adults.
of tyrosine kinases, and indirectly, through induction of the discovery that the growth hormone receptor
insulin-like growth factor 1 (iGF-1). this review addresses signals as a class 1 cytokine receptor via stat51–3 and the
the relative roles of growth hormone and iGF-1 in mediat- presence of growth hormone receptors in virtually every
ing their biological effects, as well as the clinical outcome cell of the body have led to the realization that growth
of inappropriate growth hormone signaling. Furthermore, hormone acts not only through its classical mediator
it summarizes novel information provided by transgenic iGF-1 but also through many additional signaling pro-
mouse models and mutagenesis studies on the roles and cesses and mediators.4 moreover, like other cytokines,
mechanisms of activation of the growth hormone receptor growth hormone is produced locally in a variety of
in the context of related class 1 cytokine receptors. tissues.4 its iGF-1-independent actions are exemplified
by the several hundred transcripts that display altered
Physiological roles of growth hormone levels of expression after deletion of the growth hormone
in the past two decades, a number of animal models receptor in the murine liver, the hepatocytes of which lack
and cases of human growth deficit resulting from loss of iGF-1 receptors in the adult.5,6 one of the manifestations
growth hormone and/or iGF-1 function have provided of this deletion is extensive hepatic steatosis in mice fed
novel insights into the physiology of growth hormone a normal diet, a phenomenon also apparent in human
(Figure 1). these models include rodents with impair- growth hormone deficiency and growth hormone receptor
ment of growth hormone secretion; transgenic mice insensitivity owing to the loss of receptor function (laron
overexpressing a growth hormone antagonist; as well as syndrome). 7 other examples of iGF-1-independent The University of
Queensland, Institute
both mice and humans with loss-of-function of the growth actions mediated through the growth hormone recep- for Molecular
hormone receptor, loss of iGF-1 or of the key signaling tor are ovarian preantral follicle development,8 fusion of Bioscience, St Lucia,
Qld 4072, Australia
mediator of growth hormone, signal transducer and acti- myoblasts with nascent myotubes to increase muscle fiber (A. J. Brooks,
vator of transcription 5 (stat5). additional insight has size9 and chondrocyte generation at the growth plate.10 M. J. Waters).
activation of chondrocyte stem cells by growth hormone
Correspondence to:
competing interests was shown previously by lindahl et al.,11 and, in a study A. J. Brooks
The authors declare no competing interests. by Blackmore et al.,12 the exercise-dependent increase a.brooks@uq.edu.au

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Key points protects against excessive catabolism of proteins (used to

provide amino acids for the maintenance of glucose pro-
■ The growth hormone receptor mediates a wide range of growth-related and
metabolic actions, both directly and via insulin-like growth factor 1 (IGF-1) duction by gluconeogenesis) and, concomitantly, conserves
glucose for the brain.16 in the fed state, growth hormone
■ receptor loss-of-function, predominantly owing to mutations in the extracellular
domain, results in growth hormone insensitivity or Laron syndrome promotes anabolism by increasing the production of
insulin and iGF-1.1 through an increase in lipolysis in
■ receptor gain-of-function mutations are not known, but excessive receptor
stimulation by growth hormone leads to gigantism, adult acromegaly and cancer
fasting and insulin and iGF-1 production in the fed state,
(if autocrine growth hormone signaling is involved) growth hormone is able to increase muscle mass at the
■ The hormone–receptor complex is well-defined at a molecular level for the
expense of adipose tissue, an effect that is evident clinically
extracellular domain in the treatment of growth hormone deficiency.16
■ The growth hormone receptor exists as a constitutive dimer, and activation
the ready availability of synthetic, recombinant human
involves rearrangement of the receptor subunits to align the tyrosine-protein growth hormone has led to its use as a treatment for short
kinases JAK2 and Src bound below the cell membrane for activation stature in children, with or without concomitant growth
■ JAK2 and the Src family of proto-oncogene tyrosine-protein kinases initiate hormone deficiency (table 1).17–29 its effects on anabolism
signaling, the former involving the key transcription factor signal transducer have also been found beneficial for disorders unrelated to
and activator of transcription 5b short stature, for example, in patients undergoing chronic
hemodialysis,30 as well as to prevent muscle wasting in
adults with acquired immunodeficiency syndrome,
– in whom growth hormone is also able to increase pro-
IGF-1 GH
duction of CD4-positive t cells.31 Clear evidence shows
that treatment with growth hormone improves cardio-
+
vascular health, exercise capacity and mental outlook in
Immune Lipolysis
function Insulin resistance growth hormone-deficient adults.32–35 moreover, treat-
ment of gonadotropin-resistant women undergoing
Skeletal muscle Renal function Chondrocyte Bone, tooth Insulin in vitro fertilization with growth hormone improves
proliferation synthesis
hypertrophy pregnancy rates.36
Cardiovascular Gastrointestinal Reproduction Neurogenesis Hepatic
endothelium metabolism growth hormone antagonism
Pathologic actions of growth hormone are evident clini-
Figure 1 | Major physiological actions of growth hormone and insulin-like growth
cally in adults with growth hormone excess (that is, acro-
factor 1 action. Given that growth hormone uses signal transducer and activator of
transcription 5 (STAT5) to induce both IGF-1 and for many of its direct actions, it is
megaly owing to tumors arising from somatotrope cells
difficult to attribute specific roles to growth hormone or IGF-1 for many biological of the pituitary gland) with its associated increases in
effects. However, those actions which involve more direct growth hormone action mortality and morbidity. if untreated, individuals with
are placed to the right, whereas those involving induced IGF-1 to the left, acromegaly can die early from cardiovascular and renal
acknowledging that these assignments may change. Note that the growth failure, preceded by neuropathy from cartilage overgrowth
hormone–IGF-1 system is regulated by the tight negative feedback loop between owing to carpal tunnel syndrome.2,37 symptoms are allevi-
hepatic IGF-1 production and pituitary growth hormone secretion. Abbreviations: ated by surgery, radiotherapy, treatment with analogs of the
GH, growth hormone; IGF-1, insulin-like growth factor 1.
growth hormone-inhibiting agent somatostatin, the very
effective growth hormone receptor antagonist pegvisomant
in neural stem cell number, which overcomes their age- or by combinations of these therapeutic approaches.37 in
dependent decline, was shown to be absent in mice with patients with type 1 diabetes mellitus, who have markedly
gene inactivation (knockout) of the growth hormone elevated levels of circulating growth hormone, somato-
receptor. again, in vitro studies13 indicate that neural statin analogs can slow the progression of proliferative
stem cell activation by growth hormone does not require retinopathy,38 analogous to the effects that antisense oligo-
iGF-1. accordingly, although iGF-1 treatment of patients nucleotides against the growth hormone receptor mrna
with mutations in the growth hormone receptor can par- have on oxygen-induced retinopathy in mice.39 these
tially restore linear growth, final height never reaches the observations are in agreement with results obtained from
level seen with growth hormone replacement in patients the, now historical, pituitary removal used to slow progres-
with growth hormone deficiency.14 similarly, mice that sion of retinopathy in type 1 diabetes mellitus.40 moreover,
lack both growth hormone receptor and iGF-1 expression convincing data from animal studies indicate that many
are substantially smaller than mice lacking only iGF-1.15 cancers are growth-hormone-dependent,41 and pegvi-
nevertheless, iGF-1 is absolutely required for linear somant has been shown to reduce the growth of human
growth and many other processes, such as development breast and colorectal xenografts in animal models.42,43
of committed neural and chondrocyte progenitor cells.
The growth hormone receptor
clinical applications of growth hormone Cloning of the gene sequence of the human growth
Growth hormone is the major determinant of postnatal hormone receptor enabled mapping of its 10 exons, nine
growth; however, this important metabolic hormone is of which are coding, to chromosome 5p13, including
also instrumental in the switch from glucose to fatty acids exons 1–7 that correspond to the extracellular domain of
as a source of fuel during periods of fasting. this switch the receptor.44 Crystallization of the hormone–receptor

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complex 45 showed that the extracellular portion of the Table 1 | Clinical use of recombinant human growth hormone
growth hormone receptor protein consists of the minimal indications study reference
structural elements for a class 1 cytokine receptor, includ-
Current applications
ing two β-sheet sandwich fibronectin iii domains located
above a single transmembrane sequence. each fibronectin Children born small for gestational age Simon et al.17, Labarta et al.18
iii domain contributes a key tryptophan residue in a Pituitary insufficiency during childhood Bakker et al.19
precise orientation, which allows growth hormone, which Children with chronic kidney disease, including Hokken-Koelega et al.20,
comprises a four-helix bundle, to be locked into place autosomal recessive polycystic kidney disease Mehls et al.21
through strong hydrophobic interactions with the recep- SHOX deficiency Blum et al.22
tor (Figure 2).46 Binding of growth hormone to its receptor Idiopathic short stature Bryant et al.23, Cohen et al.24
occurs initially via site 1 (helix 4 and the helix 1–2 loop),
Noonan syndrome romano et al.25
then via site 2 (helix 3 and the n-terminus). Hormone
binding is consolidated by association of the two recep- Turner syndrome Davenport et al.26

tors, which form a homodimer, through the dimeriza- Prader–Willi syndrome Goldstone et al.27, Burman et al.28
tion domain in the lower fibronectin iii module. within Juvenile idiopathic arthritis on glucocorticoid therapy Simon et al.29
the larger cytoplasmic domain, and proximal to the cell Adult growth hormone deficiency (improved Burger et al.32, Boschetti et al.33,
membrane, is a proline-rich box 1 sequence that binds cardiovascular risk and function, exercise capacity, Widdowson et al.34, Saller et al.35
the protein tyrosine kinase JaK2, largely constitutively. mental outlook and quality of life)
Key tyrosine residues are phosphorylated by the acti- Improvement in successful pregnancy rate in poor Kolibianakis et al.36
vated JaK2, leading to signal transduction, particularly gonadotropin responders for IvF
via phosphorylated stat5b (Figure 3).46,47 Promising applications
Children with Crohn disease Denson135
The receptor activation mechanism Patients with cystic fibrosis Denson135
the growth hormone receptor and homologous homo-
renal and/or liver transplant Fuqua136
dimeric cytokine receptors, such as prolactin, thrombo-
poietin and erythropoietin receptors, activate the Chronic hemodialysis patients (reduced mortality) Feldt-rasmussen et al.30
JaK2–stat pathway upon ligand binding. However, Fibromyalgia Cuatrecasas137
the exact means used by the ligand to activate this path- AIDS wasting and thymic atrophy (increased CD4+ Tesselaar et al.31
way via its receptor remain unclear. analysis of the crystal T-cell production)
structure of growth hormone bound to the extracellular Frail elderly with chronic kidney disease Abdel-rahman et al.138
domain of the growth hormone receptor, together with Abbreviations: AIDS, acquired immunodeficiency syndrome; IvF, in vitro fertilization; SHOX, short stature
binding kinetics, demonstrated that one growth hormone homeobox protein.

molecule binds to the extracellular domains of two growth

hormone receptor molecules via two asymmetrically placed growth hormone, and that dimerization alone is not suffi-
binding sites, with hormone binding being stabilized by cient to initiate signaling from the growth hormone recep-
a third receptor–receptor interaction.45–47 the original tor.50–52 Constitutive dimerization has also been shown for
activation hypothesis proposed that growth hormone the prolactin receptor 53 and erythropoietin receptor.54,55 to
bound to a single monomeric growth hormone receptor date, the most widely accepted model for growth hormone
on the cell surface and subsequently induced dimerization receptor activation proposes that growth hormone binding
of the growth hormone receptor by recruiting a second induces a conformational change in the constitutive dimer
growth hormone receptor through interaction at site 2.48 of the growth hormone receptor, which includes rotation
this model was based on early studies using the purified of one growth hormone receptor subunit relative to the
extracellular domain of the growth hormone receptor and other, with locking together of the extracellular receptor–
in vitro studies with three anti-growth hormone recep- receptor interaction domain (Figure 4).50 this rotation
tor antibodies, which utilized a chimera of the growth model of growth hormone receptor activation is sup-
hormone receptor and the granulocyte–macrophage ported by biochemical studies, receptor epitope mapping
colony-stimulating factor (Gm-CsF) receptor for signal- for an agonist antibody and comparison of the receptor
ing studies. ligand-induced dimerization was proposed crystal structures in the presence and absence of growth
to bring the intracellular domains of the growth hormone hormone.50,56 this model has been strengthened further
receptor together, allowing JaK2 bound at the box 1 by computer simulations, which showed a relative subunit
motif to activate by transphosphorylation, as for receptor rotation as the result of removing the hormone from the
tyrosine kinases, such as the insulin receptor.48,49 2:1 complex.57 such subunit rotation models of activation
this mechanism of growth hormone receptor acti- have been proposed for many receptors, including the
vation became the paradigmatic activation model for prolactin receptor 58 and the erythropoietin receptor.59–63
class 1 cytokine receptors. However, studies could sub-
sequently show, using a variety of techniques including JAK2 and Src family kinase signaling
fluorescence resonance energy transfer, bioluminescence JaK2 has been regarded as the classical growth hormone
resonance transfer and co-immunoprecipitation, that the receptor signaling kinase.3 now, strong evidence indi-
growth hormone receptor expressed on the cell surface is cates that activation of the growth hormone receptor also
predominantly constitutively dimerized in the absence of results in direct activation of src family kinases (sFKs),65,66

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in the crystal structures, which differs between agonist-

Site 1 bound and antagonist-bound forms of the receptor, and
mutating this loop markedly decreased erK signaling but
Arg71 Site 2 not JaK2–stat5 signaling.65
Arg71 of interest, the F–G loop is adjacent to a conserved
Phe96 Glu44 YGeFs motif in the lower fibronectin module of the
Tyr86 Val125
Phe96
extracellular domain the growth hormone receptor,
Cys94 Glu42 Tyr86
Ser40
Val125
Cys94
which is equivalent to the wsXws sequence—a motif in
Glu44
Trp50 Cys38 Arg161 Ser40
Cys38
Trp50
the extracellular domain of all class 1 cytokine receptor
Pro131 Glu42 family members. mutations within this sequence result
Tyr222 Prc131
Glu224 Tyr222
in growth hormone insensitivity and laron syndrome
Ser226 Arg161 (see below). supporting the duality of growth hormone
Val155 Glu224
receptor signaling, studies on the erythropoietin receptor,
Arg211 Gln154
Ser226 using different extracellular domain activation conforma-
Ile153
Asp152
Arg211 tions in conjunction with alanine insertions, at the boun-
Val155
Tyr208 dary between transmembrane domain and cytoplasmic
Val144 Gln154
His150 Ile153 Tyr208
domain which introduce helical rotations, showed
Asp152 differential stat5 to erK activation.72 these data again
His150 show that conformational changes in the extracellular
Val144 domain and rotation of the transmembrane domain are
critical activation mechanisms for these receptors.
Figure 2 | Locations of known point mutations in the extracellular domain of the
human growth hormone receptor associated with impaired postnatal growth. JAK2 activation
The yellow ribbon represents growth hormone, the green ribbon is the first growth
while progress has been made in understanding the con-
hormone receptor and the blue ribbon shows the second growth hormone receptor.
Binding of growth hormone to its receptor occurs initially via site 1 (helix 4 and the formational changes required for activation of the growth
helix 1–2 loop), then via site 2 (helix 3 and the N-terminus). A residue at Glu207 is hormone receptor; the mechanism by which these con-
the beginning of a 36-amino acid insertion reported by Maamra et al.140 that does formational changes result in JaK2 activation remains
not seem to influence receptor dimerization. The red residues are those for the elusive. JaK2 is made up of four major domains, an
conserved YGEFS motif. All residues listed are wild-type. A full listing of wild-type and n-terminal Ferm (4.1 protein, ezrin, radixin and moesin)
mutant residues is given in Savage et al.93 domain followed by sH2 (src homology 2), pseudokinase
and kinase domains.73 JaK2 binds to the box 1 motif 3 of the
although the strength of the relative JaK2 and sFK signals growth hormone receptor largely via its Ferm domain.74
is dependent on cell type.64,65 activation of sFKs by ligand the catalytic domain of the JaK2 kinase is normally held
binding has also been shown for the related erythropoietin in an inactive state by autoinhibition through interactions
receptor, prolactin receptor and thrombopoietin recep- with its pseudokinase domain.75 in human leukemia, a gene
tor.67–70 the activation of sFKs by growth hormone does fusion between the oncogenic transcription factor etv6
not require JaK2 activation,65 as also reported for prolactin (also known as tel) and JaK2 is often observed. the cata-
activation of the prolactin receptor.70 sFK activation by lytic domain of JaK2 is fused with the oligomerization
growth hormone was shown to activate mitogen-activated domain of tel, which produces a constitutively active
protein kinase 1 (also known as extracellular signal- kinase molecule. the oligomerization domain of tel is
regulated kinase 2 [erK2]) and mitogen-activated protein required for the kinase activity, implying that the kinase
kinase 3 (also known as erK1) through a phospholipase domains must be held in close proximity to be activated.76
Cγ–ras pathway (Figure 3).65 the erythropoietin receptor the JaK2 val617Phe mutation, found in the majority
has similarly been shown to activate an sFK which signals of patients with myeloproliferative disorders (for example,
through phospholipase Cγ2.71 polycythemia vera),77 is thought to disrupt the inhibitory
Barclay et al.6 have described targeted knock-in muta- pseudokinase interaction, which allows the catalytic
tions to the box 1 sequence of the growth hormone recep- domain to be constitutively active.78 However, this activity
tor in mice, which abrogated JaK2 activation by growth is only observed in the presence of a dimerized receptor
hormone in vivo, but did not decrease activation of hepatic scaffold,79 again supporting an activation mechanism in
erk via src. these mice displayed an mrna expression which the JaK2 kinase domains must be released from the
profile differing from that of mice harboring a deletion of pseudokinase domain and brought into close proximity.
the growth hormone receptor gene, including several tran- JaK2 mutational analysis studies have identified many
scripts regulated by erK. relevant to the receptor activa- constitutive active mutants in the pseudokinase domain
tion mechanism, perturbing the relative orientations of the and suggested that the sH2-pseudokinase domain linker
two transmembrane helices of the growth hormone recep- is important for transmitting the ligand binding signal by
tor with glycine and proline substitutions changed the ratio flexing a hinge within the pseudokinase domain.80
of JaK2–stat5 to erK signaling.65 moreover, a specific
conformational change in the loop between the β-strands F The receptor transmembrane domain
and G of the lower fibronectin module of the extracellular Given that conformational change induced by ligand
domain of the growth hormone receptor was identified binding activates JaK2, these structural changes must

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Cytoplasm RAP
STAT1
JAK2 Src PLCγ RAS
STAT1 STAT3
IRS SHC
STAT1 GRB PKC RAS JNK
STAT1 SOS GRF
mTOR PI3K
STAT3 MEK
STAT5 ERK
STAT5 Cytosolic
STAT5 targets

Transcription of target genes

Nucleus
Growth and metabolism

Figure 3 | Signaling pathways of growth hormone. The extent of the individual pathways varies between cell types, depending
on the relative expression of the component parts. Canonical protein-tyrosine kinase JAK2 signaling via STAT5 involves
phosphorylation of key tyrosine residues in the cytoplasmic domain (below residue 350), which bind the Src homology 2 (SH2)
domain of STAT5A and STAT5B, recruiting these STATs to the activated JAK2 and thus facilitating their tyrosine
phosphorylation and subsequent dimerization through their SH2 motifs. Dimerized STAT5 translocates to the nucleus to
regulate gene transcription in complex ways. Conversely, STAT1 and STAT3 undergo direct tyrosine phosphorylation by JAK2
without the requirement for receptor binding. ErK can be activated either by SrC and/or phospholipase Cγ and ras, or by
JAK2 via the adaptors SHC, GrB and SOS. JNK is activated by SrC via rAP. The PI3K and the serine–threonine-protein
kinase mTOr pathway is activated by JAK2 via IrS phosphorylation. Signals are initially damped or terminated by the action
of specific tyrosine phosphatases and receptor internalization, then by the actions of induced SOCS proteins, particularly
SOCS2.139 Abbreviations: ErK, extracellular signal-regulated kinase (also known as mitogen-activated protein kinase); GrB,
growth factor receptor-bound protein; IrS, insulin receptor substrate; JAK2, Janus kinase 2; JNK, c-Jun N-terminal kinase;
MEK, dual specificity mitogen-activated protein kinase kinase 2; mTOr, mammalian target of rapamycin; PI3K,
phosphoinositide 3-kinase; PLCγ, phospholipase Cγ; rAP, ras-related protein; rASGFr, ras-specific guanine nucleotide-
releasing factor; SHC, SH2-domain containing transforming protein; SOCS, suppressor of cytokine signaling; SOS, son of
sevenless; SrC, proto-oncogene tyrosine-protein kinase Src; STAT, signal transducer and activator of transcription.

be transmitted through the transmembrane domain and eltrombopag (previously known as sB497115), interact
intervening sequences from the extracellular domain to only with residues within the transmembrane domain and
the box 1 motif (Figure 4). the constitutive dimeriza- extracellular juxtamembrane linker,86–88 which underscores
tion of the growth hormone receptor 50 and the erythro- the role of the transmembrane domain as an important
poietin receptor 55 is mediated predominantly through target for novel drug development to modulate cytokine
interactions in the transmembrane domain; however, and growth hormone receptor activation.
other regions such as the extracellular dimerization Finally, intriguing evidence from clinical and experi-
domain may also play a role in the dimerization process mental studies on patients with X-linked severe com-
or provide specificity to homodimer formation.81 random bined immunodeficiency (X-sCiD)—a disorder that
mutagenesis experiments have revealed constitutive active affects lymphocytes—suggests that the common cytokine
mutations in the transmembrane domain of homologous receptor γ chain plays a critical role in stat5 activation.
erythropoietin receptor 82 and thrombopoietin receptor.83 X-sCiD results from a mutation of the gene IL2RG which
mutation ser505asn in the transmembrane domain of encodes the cytokine receptor common subunit γ. adriani
the related thrombopoietin receptor is linked to familial et al.89 have shown that growth hormone stimulation fails
essential thrombocythemia, and this mutation (also to result in phosphorylation or nuclear localization of
experimentally mutated to glutamic acid, aspartic acid stat5 in epstein–Barr virus-transformed B lymphocytes
or glutamine) results in constitutive activation of the isolated from patients with X-sCiD, even though they
receptor. these mutations in the thrombopoietin recep- express normal levels of the growth hormone receptor.
tor transmembrane domain are proposed to not only this defect seems to be restricted to stat5 signaling, as
promote dimerization but also alter the conformation no notable alteration of activation of JaK2, stat1, stat3
or rotation of the transmembrane domain to an active and erKs occurred upon growth hormone stimulation
form.84,85 additionally, several nonpeptide thrombo- compared with control cells. activation of stat5 could
poietin mimetics, for example, nP-004, sB394725, and be rescued by reconstitution of the B lymphocytes with

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together with comprehensive in vitro mutagenesis studies

(Figure 2).47,49 many are hormone-binding residues evident
from in vitro alanine scans, but some give insight into the
activation mechanism itself. in particular, the asp152His
mutation in the extracellular dimerization domain dis-
rupts signaling without alteration in the binding capacity,
which emphasizes the importance of locking the receptor
subunits together in a precise manner to initiate signal-
ing. other mutations in this region (residues 144–155)
can also disrupt dimerization, as well as trafficking to
the cell surface.94 the mutation Pro131Gln disrupts the
angle between the two domains and hormone binding to
the key tryptophan residues.95 some other mutations can
Box 1
Box 1

Box 1

Box 1
be predicted to impair folding of the fibronectin domains
or influence translocation to the cell surface (for example,
Phe96ser, arg161Cys, tyr208Cys).
intriguingly, three separate mutations (tyr222His,
Glu224asp, ser226ile) in the conserved YGeFs-sequence
Figure 4 | Model for the activation of the growth hormone receptor by growth hormone. result in laron syndrome; the role of this sequence is,
Growth hormone binding to the extracellular domain of the growth hormone receptor however, not precisely defined. it seems to be important
reorients the pre-existing homodimer so that one growth hormone receptor subunit for the stability of folding of the lower fibronectin module,
rotates relative to the other. This structural reorientation is transmitted through the
but this does not apply to the Glu224 position.96 moreover,
transmembrane domain resulting in a repositioning of tyrosine kinases bound to
the cytoplasmic domain of the receptors. Data using fluorescence resonance energy
in response to growth hormone, the receptor binds the
transfer suggests that the distance between the box 1 motifs increases between powerful coactivator and splicing protein coactivator acti-
inactive and active states141 and this movement is fundamental to activation of JAK2. vator (Coaa) via the YGeFs-motif,97 and this sequence is
also required for transcriptional activation by the receptor
wild-type cytokine receptor common subunit γ, demon- directly.97 thus, one could speculate that this conserved
strating that the defect in stat5 signaling is probably spe- sequence is key to some of the direct genomic actions of
cific. these studies suggest an important role for stat5, the growth hormone receptor. notably, no point muta-
at least in immune cells, although a broad cell-type effect tions resulting in laron syndrome have been reported in
is suggested by a study in boys (aged 12–15 years) with the transmembrane domain, which may indicate that the
X-sCiD and extreme short stature who fail to produce specificity for transmembrane domain interaction is not as
normal levels of iGF-1 in response to high doses of growth stringent as it is for interaction with the hormone. However,
hormone.90 such studies emphasize that growth hormone mutation at the transmembrane entry point (asp244asn)
receptor signaling still has clinically important levels of within the conserved CeeD sequence does result in growth
complexity which are yet to be fully understood. impairment in the context of a domain-disabling mutation
in the other copy of the receptor (tyr208Cys).98
loss-of-function mutations (laron syndrome) Below the cell membrane, mutation of the splice-
the demonstration of an altered coding sequence of the acceptor site for exon 8 results in skipping of exon 9, trun-
growth hormone receptor—the loss of exons in the extra- cation of the proline-rich box 1 sequence and a dominant
cellular domain of the cloned receptor sequence—in two negative form of the receptor with the capacity to form
patients with laron syndrome (a type of growth hormone heterodimers.99 this mutation emphasizes the impor-
insensitivity syndrome) was the first proof that this disorder tance of the conserved box 1 sequence for the activation
was the result of a defect in the growth hormone receptor.44 of JaK2, as well as the need for two JaK2 kinases for
laron syndrome is defined by an elevated level of basal intact receptor signaling; the receptor needs to exist as a
serum growth hormone, exaggerated secretory response dimer for signal generation via transactivation of the JaK2
to provocative stimuli, but low circulating concentrations catalytic domains. laron syndrome associated with cyto-
of iGF-1, iGF-binding protein 3 (iGFBP3) and usually low plasmic truncation at residue 449 but correct coding only
levels of serum growth hormone binding protein. this dis- to residue 423 emphasizes the importance of the distal
order is associated with growth retardation, and patients tyrosines in generating active stat5b.100 this observation
are typically >5 sD below normal adult height.91 over 60 is supported by a similar finding that the murine growth
growth hormone receptor loss-of-function mutations have hormone receptor, if truncated at residue 391, cannot acti-
now been reported worldwide in patients with laron syn- vate stat5b in vivo.5 similarly, a parallel exists between a
drome,92,93 but, as yet, no activating mutations have been growth hormone receptor mutant truncated to 581 amino
determined. although most mutations are nonsense or acids with a nonsense sequence of residues 560–581,
altered splicing mutations in the extracellular domain,93 which was associated with a reduced ability to activate
a number of point mutations have been useful in under- stat5b and short stature in humans,101 and a knock-in
standing the function of the receptor, particularly when mouse model expressing a mutated growth hormone
considered in the context of the landmark crystal structure receptor truncated at residue met569 (plus tyr539Phe
of the hormone–receptor extracellular domain complex,45 and tyr545Phe), which generates only 30% of the level

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of active stat5 found in wild-type mice and thus drives many signaling pathways with growth hormone. other
only 50% of normal growth hormone-dependent growth possibilities are that endocrine iGF-1 may not be as effec-
postnatally.5 the key importance of stat5 activation tive as autocrine and/or paracrine iGF-1 or that altered
in postnatal growth is exemplified by the severe growth iGFBP3 and/or iGFals levels impair the availability of
impairment in patients with STAT5b mutation, who were exogenous iGF-1.
first identified by Kofoed and colleagues.102
The d3-growth hormone receptor polymorphism
Treatment of Laron syndrome about half of the european population are either homo-
Children with laron syndrome have severe growth impair- zygous or heterozygous for a polymorphism of the growth
ment (4–10 sDs below the mean height), impaired muscle hormone receptor that leads to the deletion of exon 3
and bone development, as well as a degree of obesity and (d3-growth hormone receptor), the frequency of homo-
steatosis. these children have dysmorphic features includ- zyote alleles being around 12%.109 this polymorphism is
ing characteristic facial features (protruding forehead, the result of a retroviral insertion event and results in the
saddle nose, blue sclerae), disproportionally short limbs deletion of 22 residues near the n-terminus of the mature
and a high-pitched voice as adults.91 a deficient iGF-1 and receptor. the exon 3 polymorphism marginally increases
iGFBP3 stimulation test in response to recombinant sensitivity to recombinant human growth hormone in
human growth hormone is a primary diagnostic93 con- patients with growth hormone deficiency, resulting in
comitant with, in the case of most receptor extracellular slightly increased baseline height and an approximately
domain mutations, markedly decreased levels of serum 0.5 cm per year higher growth response than indivi-
growth hormone-binding protein, which is encoded by duals with growth hormone deficiency but without this
the growth hormone receptor gene and has been shown to polymorphism, according to the results of a large meta-
be the shed extracellular domain of the receptor.103,104 analysis.109,110 However, d3-growth hormone receptor
Humans with mutations in the growth hormone recep- does not seem to influence growth rate in healthy indivi-
tor, as well as patients with growth hormone insensitivity duals, presumably owing to compensation by the growth
resulting from mutations in STAT5 or IGF‑1, can be hormone–iGF-1 feedback system.
treated with FDa-approved recombinant iGF-1 (mecaser- the exon 3 deletion is reported to be associated with
min), with appropriate care to avoid hypoglycemic events. a lower Bmi and significantly improved glucose toler-
treatment with mecasermin produces a robust increase ance,111 yet seems to predispose to an increased morbidity,
in height gain in the first year, from around 2.8 cm to an both clinically and biochemically, in patients with acro-
average of 8.0 cm with a dose of 40 μg/kg in a study of 59 megaly.112 the mechanism for increased hormone sensi-
patients.105 this height gain can be increased to 8.7 cm tivity is unclear. Potentially, the exon 3-derived sequence
with a 120 μg/kg dose (in comparison, growth hormone sterically hinders the approach of growth hormone; this
produces a 10–12 cm height gain in isolated growth hypothesis is, however, not verifiable by crystal struc-
hormone deficiency in the first year 19). even at the higher ture analysis, as this part of the receptor is not visible in
dose, however, a marked decrease of growth stimulation published structures.
occurs in the second and subsequent years to around 5 cm
per year.106 unlike recombinant human growth hormone Growth hormone signaling and cancer
treatment of children with growth hormone deficiency, a large body of evidence implicates growth hormone and
which produces more sustained growth increases and iGF-1 in tumor progression. with the use of final height as
allows patients to reach near normal height, a normal a marker for growth hormone and iGF-1 action, a review
final height is only rarely achieved with iGF-1 therapy,14 of over 300 case–control and cohort studies113 found that
although it also improves BmD and blood cell counts. individuals >175 cm in height have a higher incidence
Patients with laron syndrome are deficient in iGFBP3 of breast cancer (22% increase), prostate cancer (20%
and iGFBP-complex acid labile subunit (iGFals), which increase) and colon cancer (20–60% increase) relative to
shortens the half-life of administered iGF-1. Hence, a individuals of <160 cm height. similarly, Danish children
complex of iGF-1 and iGFBP3 (mecasermin rinfabate), in the top quintile for height at 14 years of age have an
which shows an increased half-life and fewer adverse adjusted relative risk of over 1.5 for breast cancer, which
events than mecasermin, has been developed for treat- surpasses any other risk factor.114
ment of short stature. However, in its complex with this data would lead one to expect a decreased incidence
iGFBP3, iGF-1 seems to be even less effective for height of cancer in the absence of growth hormone. surprisingly,
increment.107 one reason for the weak growth stimulation however, in a worldwide survey of 222 individuals with
by iGF-1 could be the stem-cell activating ability of growth growth hormone receptor mutation or isolated growth
hormone, which is absent in patients with severe laron hormone deficiency, not even a single case of malignancy
syndrome. Hence, after a year of treatment, the stem cell was reported,115 whereas 338 first and second degree rela-
reserves may become depleted, reducing the proliferative tives reported a 10–24% incidence of a range of malig-
potential of chondrocytes in the growth plate. this phe- nancies. the difference in average age between the two
nomenon might be overcome by combined administra- groups (32 years versus 55 years, respectively) doubtless
tion of prolactin and iGF-1, because prolactin has been contributed to this disparity, but the apparent resistance of
shown to stimulate the proliferation of mesenchymal stem growth hormone-deficient and/or iGF-1-deficient indivi-
cell precursors in human articular cartilage108 and shares duals to cancer is supported by extensive animal studies.

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For example, the carcinogen nitrosomethylurea does not factor receptor and the interferon γ receptors133 and is
induce breast tumors in growth hormone-deficient dwarf often associated with cell transformation. a close corre-
(dw/dw) rats. Hormone replacement in these animals, with lation has been found between nuclear localization of the
either rat or bovine growth hormone, increases the tumor growth hormone receptor and hepatocyte-cell prolifera-
incidence towards normal levels, whereas discontinuation tion during recovery from partial hepatectomy, and trans-
of the growth hormone treatment results in tumor regres- location of the growth hormone receptor to the nucleus
sion.116 similar observations apply to breast cancers driven promoted cell proliferation and transformation in cell
by the sv40 virus large t antigen: in mice with a knockout models.131 nuclear localization sensitized the cells to auto-
of the growth hormone receptor, the tumors are markedly crine growth hormone and increased phosphorylation of
reduced in size and number compared to those observed nuclear stat5, which resulted in the altered expression of
in wild-type mice.117 this resistance to tumor initiation proliferation and transformation genes.131
and/or progression may be a key factor in the longevity In vitro studies showed nuclear localization of the recep-
observed in growth hormone receptor knockout mice, tor to be growth hormone-dependent.131,134 the observa-
given that they have a markedly lower extent of neoplasms, tion that binding of the growth hormone receptor to
such as adenocarcinoma and lymphoma.118 Coaa via the YGeFs-motif occurs in response to growth
these differences in tumor progression might relate to hormone97 is consistent with Coaa acting as a chaperone
the extent of iGF-1 availability, as iGF-1 has been shown to promote nuclear localization of the full-length growth
to act in vitro as a tumor promoter by increasing pro- hormone receptor, given that Coaa possesses canonical
liferation, decreasing apoptosis and by promoting angio- nuclear localization sequences, unlike the receptor.97,134
genesis and metastasis.119 in this view, both endocrine However, importin β binds directly to the extracellular
and growth hormone-dependent paracrine and auto- domain of the growth hormone receptor, and blocking anti-
crine iGF-1 contribute to tumor promotion. However, bodies to importin β prevent this binding, so the nuclear
the growth hormone receptor is a cytokine receptor, and translocation mechanism might be direct.131 Given the
other class 1 cytokine receptors such as the thrombo- rapid nuclear localization of the growth hormone recep-
poietin receptor and the Gm-CsF receptor display onco- tor in response to exogenous growth hormone (within
genic mutations,83,120 as is evident for the val617Phe JaK2 10 min), the intracellular rather than extracellular growth
mutant in patients with polycythemia vera.121 hormone receptor, is probably accessing the nucleus, pos-
indeed, as shown by Zhu et al.,122 forced expression sibly via the sec61 translocon.132,133 Finally, the receptor
of autocrine human growth hormone in mammary epi- itself is transcriptionally active in reporter assays,97 and this
thelial cells is capable of driving cell proliferation, trans- activation, together with its other nuclear actions, such as
formation and invasion, with epithelial to mesenchymal sensitization to stat5 activation, might account for the
transition (loss of adhesion and resulting migration and fact that autocrine growth hormone signaling is required
infiltration of single cells into neighboring tissues). this for oncogenesis to occur.
phenomenon is associated with increased angiogenesis in
xenografts.123 Perry et al.124 have extensively documented Conclusions
the dysregulation of gene expression involved in this auto- major advances, both mechanistically and clinically, have
crine growth hormone-dependent oncogenesis (such as been achieved over the past two decades in understanding
increased expression of homeobox protein Hox-a1, the functions of the growth hormone receptor. many of its
decreased junction plakoglobin and stabilization of physiological roles, the genes it regulates and the signal-
telomerase), together with altered Dna methyltransferase ing pathways used for this purpose are increasingly well
activity. they have also reported the presence of autocrine understood. moreover, a precise molecular understanding
growth hormone in breast in situ carcinoma and invasive of how the hormone binds to its receptor and a model for
ductal carcinoma,125 supporting an earlier study from mol its activation mechanism are available. Clinically, a spe-
and colleagues.126 this restriction of oncogenic effect to cific receptor antagonist and a wide variety of new clinical
autocrine growth hormone partly explains the relatively applications for growth hormone therapy now exist. in the
minor increase in cancer incidence seen during growth future, we can expect small molecule agonists and antago-
hormone replacement therapy, with a twofold increase nists, tissue-specific deletion of the receptor and many sur-
in the rate ratio of secondary neoplasms being reported in prises to provide novel understandings of the physiological
cancer survivors.127 actions of this pleiotrophic cytokine.

receptor nuclear localization Review criteria

a local oncogenic effect of growth hormone implies action
A search for original articles published between 1985 and
via the growth hormone receptor, whose expression is
2010 and focusing on growth hormone receptor was
increased in a number of different types of cancer.128,129 performed in PubMed. The search terms used were
of particular interest has been the nuclear localization of “growth hormone receptor”, “growth hormone (GH)
growth hormone receptors in many cancers, for example, review”, “erythropoietin receptor”, “prolactin receptor”,
melanoma, 129 hepatocellular cancer 130 and Hodgkin “thrombopoietin receptor/mpl” and “JAK2,” and specific
lymphoma.131 the translocation of a transmembrane combinations of growth hormone and clinical syndromes
deriving from these searches. The resulting references
protein into the nucleus is known to occur for the epi-
were used as leads for further literature searches.
dermal growth factor receptor,132 the fibroblast growth

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115. Shevah, O. & Laron, Z. Patients with congenital hormone receptor is expressed in human breast M. J. Waters is supported by grants from the Australian
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(2006). melanoma. Anticancer Res. 19, 1919–1931 A. J. Brooks and M. J. Waters researched the data for
116. Shen, Q. et al. Advanced rat mammary cancers (1999). the article and both provided a substantial contribution
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148, 4536–4544 (2007). of growth hormone and prolactin receptors in M. J. Waters contributed equally to writing the article
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