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7532.Frank S. Messina J. - Growth Hormone Receptor (2002).pdf

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Growth Hormone
Receptor
Stuart J. Frank1,* and Joseph L. Messina2
1
Department of Medicine, Division of Endocrinology and Metabolism, and Departments of Cell Biology
and Physiology, University of Alabama at Birmingham, and Veterans Affairs Medical Center, 1530 3rd
Avenue South, BDB 861, Birmingham, AL 35294-0012, USA
2
701 South 19th St., LHRB Room 531, Birmingham, AL 35294, USA
* corresponding author tel: (205) 934-9877, fax: (205) 934-4389, e-mail: frank@endo.dom.uab.edu
DOI: 10.1006/rwcy.2002.1418.
SUMMARY
The growth hormone receptor (GHR) is believed to
be required for all of the growth promoting and
metabolic activities of growth hormone (GH). The
GHR is widely expressed among species and is a
single membrane-spanning receptor in the cytokine
receptor superfamily. GH-induced homodimerization
of the GHR causes activation of the receptorassociated cytoplasmic tyrosine kinase JAK2.
Multiple signaling pathways, including the STAT,
MAP kinase, and PI-3 kinase pathways are downstream of GH-induced JAK2 activation and have
been linked to expression of GH-activated genes and
GH-induced alterations in cell behavior. STAT5b, in
particular, has been shown to mediate important
sexually dimorphic effects of GH that correlate with
the pulsatile pattern of GH release from the pituitary
gland. Clinical disorders arising from deficient or
excessive GH action are well described and in some
instances are related to aspects of GHR function and/
or can be pharmacologically approached based on the
accumulated knowledge concerning the GH±GHR
interaction. GHBP, a high-affinity circulating GHbinding protein corresponding to the GHR extracellular domain, arises in some species by alternative
RNA splicing and in others by proteolytic shedding
Cytokine Reference
from the full-length GHR. GHBP's significance in
GH physiology and signaling is as yet unclear.
BACKGROUND
Discovery
Early characterization of specific binding sites for
GH utilized cell lines such as the human IM-9 B
lymphocyte or rabbit liver (Van Obberghen et al., 1976;
Waters and Friesen, 1979). While widely distributed,
GHR is most abundantly expressed in liver. The first
GHR cDNA clone was isolated in 1987 from human
and rabbit liver after purification using anti-GHR
monoclonal antibodies (Leung et al., 1987). cDNAs
encoding the rodent (mouse and rat) (Baumbach et al.,
1989; Smith et al., 1989), ruminant (cow and sheep)
(Adams et al., 1990; Hauser et al., 1990), pig (Cioffi et
al., 1990), and chicken (Burnside et al., 1991) GHRs
were cloned thereafter in 1989±1991.
Alternative names
Because of its role in growth promotion, GH is
sometimes called somatotropin. Thus, the GHR is
Copyright # 2002 Published by Elsevier Science Ltd
2
Stuart J. Frank and Joseph L. Messina
also known as the somatogenic receptor or the
somatotropin receptor.
Structure
The GHR is a single membrane-spanning type 1
glycoprotein member of the cytokine receptor superfamily (Bazan, 1990). The features shared with that
large family of receptors include in the ligand-binding
extracellular domain the characteristic placement of
cysteine residues and the WSXWS-like motif, and
in the cytoplasmic domain the proline-rich Box 1
element involved in association with Janus kinases.
The GHR is in the subgroup of cytokine receptors
that are thought to contain only one type of protein.
That is, some members exist in their active (liganded)
state as heterodimers or heterooligomers, but the
GHR ± like PRLR, thrombopoietin receptor, EPOR,
and leptin receptor ± instead forms a homodimer.
Full-length GHRs from various species are in the
range of 600 amino acids in length (620 residues in the
mature human GHR) and contain relatively large
cytoplasmic domains (350 residues in the human).
Several alternatively spliced forms of the GHR
encode receptors that differ from the full-length
GHR. In rodents, the full-length GHR is encoded by
a 4.2±4.7 kb message, while an alternatively spliced
mRNA of 1.0±1.4 kb encodes a shortened GHR
(Smith et al., 1989; Baumbach et al., 1989). This
variant has the extracellular domain in common with
the full-length receptor, but has the transmembrane
and cytoplasmic domains replaced by a short
hydrophilic amino acid stretch that confers secretion
to this isoform, which then circulates as a highaffinity GH-binding protein (GHBP) (more below).
mRNAs that predict truncated membraneanchored GHR isoforms have been described that
encode the extracellular and transmembrane
domains, but only have several intracellular residues
(Dastot et al., 1996; Ross et al., 1997). These
relatively low-abundance mRNA variants arise by
alternative splicing and by frameshifting to yield the
truncated receptor forms. Their exact physiological
significance is as yet not known. Another variant
GHR found only in humans lacks the 22 extracellular
domain residues encoded by exon 3 (66 base pairs) of
the human GHR gene. This interesting variant was
first thought to arise from alternative splicing
(Urbanek et al., 1992). A recent study suggested
instead that it arises from an ancestral homologous
recombination between two retroelements in intronic
sequences surrounding exon 3 only in humans (Pantel
et al., 2000). The allele for the exon 3 receptor is
found at a frequency of 25% compared with 75% for
the full-length allele (Pantel et al., 2000). As yet, no
clear difference in GH-binding affinity or function
has been determined for the exon 3 GHR form.
Main activities and
pathophysiological roles
All known activities of GH are believed to be
mediated by the GHR. The most apparent actions of
GH relate to its promotion of longitudinal growth
and muscle mass. Elevated levels of GH, such as
result from pituitary tumors that hypersecrete the
hormone, yield the clinical syndrome of acromegaly.
Acromegalics manifest bony and connective tissue
overgrowth and visceromegaly. If present prior to
pubertal epiphyseal closure, acromegaly results in
excessive height and is referred to as gigantism. GH
deficiency or GH resistance due to GHR mutations
results in shortness of stature. As described in the
chapter on GH, the GHR also mediates the many
metabolic effects of GH.
GENE
Accession numbers
Human GHR: NM_000163
Rabbit GHR: AF015252
Mouse GHR: MM010284
Rat GHR: X16726
Bovine GHR: X70041
Ovine GHR: M89912
Porcine GHR: X54429
Chicken GHR: M74057
Sequence
Figure 1 shows the nucleotide sequence of the human
GHR full-length cDNA.
Chromosomal location and linkages
The gene that encodes the human GHR is present in a
single copy on chromosome 5p13-p12 (Godowski
et al., 1989; Barton et al., 1989). It spans roughly
90 kb and contains nine coding exons (exons 2±10)
(reviewed in Schwartzbauer and Menon, 1998;
Edens and Talamantes, 1998). Exon 2 encodes some
50 UTR sequence, the signal sequence (18 residues),
and the first five residues of the extracellular domain
Growth Hormone Receptor 3
Figure 1 Coding region cDNA sequence of the human GHR. Predicted leader sequence-encoding region
is underlined in bold. Predicted transmembrane-encoding region is italicized and underlined in bold. Stop
codon (TAG) is indicated.
atggatctctggcagctgctgttgaccttggcactggaggatcaagtgatgctttttctggaagtgaggccacagcagctat
ccttagcagagcaccctggagtctgcaaagtgttaatccaggcctaaagacaaattcttctaag gagcctaaattcaccaagtgc
cgttcacctgagcgagagactttttcatgccactggacagatgaggttcatcatggtacaaaga acctaggacccatacagctgt
tctataccagaaggaacactcaagaatggactcaagaatggaaagaatgccctgattatgtttctgctggggaaaacagctgtta
ctttaattcatcgtttacctccatctggataccttattgtatcaagctaactagcaatggtggtacagtggatgaaaagtgtttctctgt
tgatgaaatagtgcaaccagatccacccattgccctcaactggactttactgaacgtcagttta actgggattcatgcagatatcca
agtgagatgggaagcaccacgcaatgcagatattcagaaaggatggatggttctggagtatgaa cttcaatacaaagaagtaaa
tgaaactaaatggaaaatgatggaccctatattgacaacatcagttccagtgtactcattgaaa gtggataaggaatatgaagtgc
gtgtgagatccaaacaacgaaactctggaaattatggcgagttcagtgaggtgctctatgtaac acttcctcagatgagccaattt
acatgtgaagaagatttctactttccatggctcttaattattatctttggaatatttgggctaacagtgatgctatttgtattcttattttct
aaacagcaaaggattaaaatgctgattctgcccccagttccagttccaaagattaaaggaatcgatccagatctcctcaaggaag
gaaaattagaggaggtgaacacaatcttagccattcatgatagctataaacccgaattccacag tgatgactcttgggttgaattta
ttgagctagatattgatgagccagatgaaaagactgaggaatcagacacagacagacttctaag cagtgaccatgagaaatca
catagtaacctaggggtgaaggatggcgactctggacgtaccagctgttgtgaacctgacattctggagactgatttcaatgcca
atgacatacatgagggtacctcagaggttgctcagccacagaggttaaaaggggaagcagatctcttatgccttgaccagaaga
atcaaaataactcaccttatcatgatgcttgccctgctactcagcagcccagtgttatccaagcagagaaaaacaaaccacaacc
acttcctactgaaggagctgagtcaactcaccaagctgcccatattcagctaagcaatccaagttcactgtcaaacatcgactttta
tgcccaggtgagcgacattacaccagcaggtagtgtggtcctttccccgggccaaaagaataag gcagggatgtcccaatgtg
acatgcacccggaaatggtctcactctgccaagaaaacttccttatggacaatgcctacttctgtgaggcagatgccaaaaagtg
catccctgtggctcctcacatcaaggttgaatcacacatacagccaagcttaaaccaagaggacatttacatcaccacagaaagc
cttaccactgctgctgggaggcctgggacaggagaacatgttccaggttctgagatgcctgtcccagactatacctccattcatat
agtacagtccccacagggcctcatactcaatgcgactgccttgcccttgcctgacaaagagtttctctcatcatgtggctatgtgag
cacagaccaactgaacaaaatcatgccttag
N-terminus. Exons 3±7 encode almost the entire
remainder of the extracellular GH-binding domain
(except when exon 3 is deleted, as above). Exon 8
encodes the 24-residue transmembrane domain and a
few residues on each of the extracellular and
intracellular domain sides flanking it. Exons 9 and
10 encode the remainder of the cytoplasmic domain
and 2 kb of the 30 UTR.
The arrangement of the mouse GHR gene exons is
quite similar to that of humans with the exception of
exon 4B, an extra 8 amino acid-encoding exon not
found in other species, and exon 8A, an exon
alternatively spliced in rodents to yield the GHBP, as
above (Edens et al., 1994; Zhou et al., 1994). The
significance of the exon 4B amino acids, if any, is as
yet unknown. GHR mRNAs from various species
exhibit substantial heterogeneity of 50 UTRs that
arises from alternative exon 1 splicing, the significance of which is also as yet unknown (Schwartzbauer
and Menon, 1998; Edens and Talamantes, 1998).
PROTEIN
Accession numbers
Human GHR: P10912
Rabbit GHR: P19941
Mouse GHR: P16882
Rat GHR: P16310
Bovine GHR: P79108
Ovine GHR: Q38575
Porcine GHR: P19756
Chicken GHR: Q02092
Sequence
Figure 2 shows the protein sequence of the human
GHR full-length cDNA.
Description of protein
As mentioned above, the GHR is an N-glycosylated
surface receptor that spans the membrane only once
and is in the cytokine receptor superfamily. The
human GHR extracellular domain is predicted to
extend from residues 1 to 246 (this numbering begins
at the first residue of the mature GHR that results
after removal of the 18 amino acid signal sequence).
Its overall structure is shown in Figure 3A. Cocrystallization and structural examination of the
bacterially expressed recombinant (nonglycosylated)
nearly complete hGHR extracellular domain (ECD)
(residues 1±238) complexed to hGH by de Vos and
colleagues (1992) provided a great deal of detailed
information as to the GHR's topography and the
nature of its interaction with the hormone (Figure 3B).
GH is composed of four antiparallel helical bundles
connected by loops of variable length and possesses
4
Stuart J. Frank and Joseph L. Messina
Figure 2 Amino acid sequence of the human GHR. Predicted leader sequence ( 18 to 1) is
underlined. Predicted transmembrane domain is italicized and underlined in bold. The Box 1 region of
the cytoplasmic domain is underlined in bold.
-18
51
121
191
261
331
401
471
541
611
mdlwqlll tlalagssda fsgseataai lsrapwslqs vnpglktnss kepkftkcrs peretfschw
tdevhhgtkn lgpiqlfytr rntqewtqew kecpdyvsag enscyfnssf tsiwipycik ltsnggtvde
kcfsvdeivq pdppialnwt llnvsltgih adiqvrweap rnadiqkgwm vleyelqyke vnetkwkmmd
pilttsvpvy slkvdkeyev rvrskqrnsg nygefsevly vtlpqmsqft ceedfyfpwl liiifgifgl
tvmlfvflfs kqqrikmlil ppvpvpkikgidpdllkegkleevntilai hdsykpefhs ddswvefiel
didepdekte esdtdrllss dhekshsnlg vkdgdsgrtsccepdiletdfnandihegtsevaqpqrlk
geadllcldq knqnnspyhd acpatqqpsv iqaeknkpqp lptegaesth qaahiqlsnp sslsnidfya
qvsditpags vvlspgqknk agmsqcdmhp emvslcqenf lmdnayfcea dakkcipvaphikveshiqp
slnqediyit teslttaagr pgtgehvpgs empvpdytsihivqspqgli lnatalplpd keflsscgyv
stdqlnkimp
Figure 3 GHR protein structure and the GH±GHR complex. (A) Diagram of the human GHR protein
structure. See text for details. Extracellular, transmembrane, and cytoplasmic domains are indicated. The
extracellular subdomains 1 and 2, as well as the hinge and juxtamembrane regions, are also shown. The
postions of the intrachain cysteine-mediated disulfide linkages present extracellular subdomain 1 in
GHRs of all species are indicated by pairs of joined C residues. YGEFS is the WSXWS-like equivalent of
the GHR. The positions of the Box 1 and UbE motifs (see text) and the conserved tyrosine residues (Y) in
the cytoplasmic domain are shown. (B) Cartoon of the crystallographically-determined structure of GH
bound to the soluble GHR extracellular domain. The structural features of the GHR extracellular
domain are indicated, as described in the text. Sites 1 and 2 of GH, which are quite distinct, interact with
very similar contact points on each GHBP molecule to result in the GH : GHBP2 complex shown. The
extensive inter-GHBP dimerization interface is indicated. This diagram is based on information in de Vos
et al. (1992), and is adapted from Frank (2002) with permission.
B
A
C
C
Subdomain 1
C
C
C
C
Extracellular
Domain
GH
Hinge
1
2
Subdomain 2
YGEFS
Subdomain 1
Juxtamembrane
Transmembrane
Domain
Box 1 Motif
Hinge Region
Y
UbE Motif
Subdomain 2
Cytoplasmic
Domain
Y
ECD 1
ECD 2
Y
Y
Y
Y
Dimerization
Interface
Growth Hormone Receptor 5
no axis of symmetry. Yet the GH±GHRECD complex
was found in a 1 : 2 stoichiometry with each of the two
different GH binding sites (site 1 and site 2) contacting a similar set of residues on each of the dimerized
GHR ECDs. Further studies showed that the strength
of interaction for each of these sites differed in
important ways (more below).
The crystal structure indicates that the ECD is
divided into two sandwich subdomains, referred to
as subdomain 1 (residues 1±123) and subdomain 2
(residues 128±238). Each subdomain is made up of
seven strands arranged into two antiparallel sheets. Subdomains 1 and 2 are linked by a fourresidue hinge region. The remaining ECD C-terminal
eight amino acids (residues 239±246) were not
included in the crystal structure and there is therefore no clear indication as to the structure they
adopt. The GHR's hormone binding region is
largely accounted for by residues in subdomain 1
and the inter-subdomain hinge residues. In addition,
each receptor within the GH±(GHRECD)2 complex
interacts with the other via an extensive dimerization
interface region. Six intermolecular bonds between
residues in subdomain 2 of each ECD occupy a
binding area of 500 AÊ2, as compared to the site 1
GHRECD and site 2 GHRECD binding areas of
1230 AÊ2 and 900 AÊ2, respectively.
Other notable ECD features present in the GHR
include six conserved cysteine residues (three pairs
that engage in intramolecular disulfide linkages), and
a WSXWS-like motif. The latter motif is conserved in
cytokine receptors and has the sequence YXXFS in
mammalian GHRs. Studies indicate that both the
intrachain disulfide linkages and the WSXWS-like
motif in the GHR are likely critical to the structural
integrity of the receptor ECD without being involved
in binding of GH (Fuh et al., 1990; Baumgartner
et al., 1994). ECD glycosylation does not appear
critical to GH binding either; bacterially expressed
(nonglycosylated) GHR ECD binds GH with an
affinity similar to that of glycosylated GHBP isolated
from serum (Fuh et al., 1990).
In contrast to the ECD, there exists no structural
information regarding the GHR cytoplasmic domain.
However, several features of this roughly 350 residue
domain are known and quite relevant to GHR
signaling and trafficking. Like other cytokine
receptors, the GHR membrane proximal cytoplasmic
domain harbors a proline-rich sequence (ILPPVPVP
in mammalian GHRs) called Box 1, which is critical
for association with JAK2. A short acidic stretch
analogous to the Box 2 domains of other cytokine
receptors (Murakami et al., 1991) roughly 30 residues
C-terminal to Box 1 resides in a region likely required
for optimal JAK2 interaction (Frank et al., 1994).
Also conserved between mammalian species are six
tyrosine residues that are potential targets of GHinduced phosphorylation and are thus important in
signaling (in the human, these are residues Y314,
Y469, Y516, Y548, Y577, and Y609). GHR residues
important for GH-induced receptor internalization and degradation include a phenylalanine at
residue 346 in the rat (F327 in human), first
implicated by Allevato et al. (1995), and the highly
conserved sequence surrounding that phenylalanine,
DSWVEFIELD, which is a so-called ubiquitindependent endocytosis (UbE) motif discovered by
Strous and colleagues (Strous et al., 1996; Govers
et al., 1999; van Kerkhof et al., 2001). The UbE is
thought to mediate GH-induced GHR ubiquitination
by allowing interactions between the receptor and
ubiquitin conjugases and ligases. Though GHR
ubiquitination itself is not required, the presence
of an intact ubiquitination system and the UbE,
perhaps by allowing ubiquitination of other associated proteins, appears to foster GHR's interaction
with clathrin-coated pits and the cell's endocytic
machinery.
The GHR, like some other cytokine receptors,
migrates aberrantly in SDS±PAGE. Its expected Mr,
given its roughly 620 amino acid sequence, is roughly
70 kDa (Leung et al., 1987). However, depending on
species, it migrates under reducing conditions in the
110±140 kDa range, in each species with a diffuse
appearance (Argetsinger et al., 1993; Frank et al.,
1994). This aberrant migration is likely only partly
contributed to by glycosylation and ubiquitination
(the latter of which, in any case, is only seen in
response to GH) (Leung et al., 1987); rather, it likely
reflects nonclassical binding of SDS by these
receptors related to particular aspects of their amino
acid sequences.
Relevant homologies and species
differences
Though GH can bind the prolactin receptor (PRLR),
the reverse does not occur. Yet, among the cytokine
receptors, GHR is most structurally similar to the
PRLR. Sequence identity between the two receptors
is less than 30%, but in data derived from cocrystallization of human GH and human PRLR ECD
the 1 : 2 ligand:receptor stoichiometry and overall
structural features of the PRLR ECD are very similar
to those seen in the GH±GHR ECD crystal structure
(Somers et al., 1994; reviewed in Behncken and
Waters, 1999). Among known species, the GHRs with
most similarity are the human and rabbit (84%
6
Stuart J. Frank and Joseph L. Messina
identical). Other notable identity comparisons are
between human and rodent (roughly 70%) and
human and chicken (roughly 59%).
Affinity for ligand(s)
While estimates of affinity of GH for the GHR vary,
dissociation constants reported are generally in the
0.1±1.5 nM range. Variability is engendered to some
extent by whether the receptor component is the
extracellular ligand-binding domain alone or the fulllength receptor expressed in cells.
As mentioned above, crystallographic and mutagenetic studies strongly suggest that GH binds to the
GHR so as to cause formation of a tripartite
GH : GHR2 complex (Cunningham et al., 1991;
de Vos et al., 1992). In this model, GH site 1, which
has a higher affinity for the GHR than does site 2,
interacts with the first receptor, allowing the
sequential interaction of site 2 with the second
receptor. GHR±GHR interactions via the dimerization interface allow stabilization of this complex and
substantial evidence suggests that the dimerized
receptor is the activated GHR conformation (see
Figure 4A). It is not yet known whether the GHR
exists to any degree as a dimer in the unliganded state,
as apparently does the related erythropoietin receptor
(reviewed in Frank, 2002). If so, it is possible that the
conformation of the receptor dimer is changed by GH
(rather than the GH-induced generation of the
receptor dimer) in order to achieve the active state.
The sequential dimerization model may explain the
bell-shaped GH concentration dependence often
observed experimentally (see Figure 4B) in that at
very high GH concentrations all available GHRs are
occupied by site 1 interactions, thereby allowing less
receptor dimers to form and less effective GH action
to be seen. Site 2 GH mutants have been prepared
and function as GH antagonists in both experimental
and clinical situations (Fuh et al., 1992; Chen et al.,
1994; Flyvbjerg et al., 1999; Trainer et al., 2000).
The predominant form of pituitary-derived GH is
the 22 kDa (191 residue form). Two other somewhat
related molecules can also bind to the GHR. One is
the product of an alternatively spliced GH transcript
deleted of residues 32±46, the so-called 20K GH
(20 kDa in size). 20K GH is a minority form in
humans (perhaps 10% of GH in circulation). Its
biological significance as compared to the 22 kDa
form is unknown, but the way 20K binds to GHR is
apparently different from that of 22 kDa GH (Wada
et al., 1998; Uchida et al., 1999; Tsunekawa et al.,
2000). 20K has much lower (one-tenth) site 1 affinity
for GHR, but similar site 2 affinity. However, it is
believed that 20K induces stronger interaction
between GHR dimer interfaces than does 22 kDa
GH, compensating for 20K's diminished site 1
affinity and yielding similar overall affinities for the
two GH forms. Indeed, expression of hGHRs
mutated at certain dimerization interface residues
yielded markedly reduced proliferation in response to
20K versus 22 kDa GH and 20K is less apt to form a
stable 1 : 1 complex with GHR, instead engaging
almost exclusively in a 1 : 2 complex. In cell culture
experiments, 20K and 22 kDa GH promote proliferation of GH-dependent cells similarly at lower
concentrations but 20K exhibits less self-inhibition
at higher concentrations.
The other non-GH ligand for the GHR is the
placentally derived hormone placental lactogen (PL).
PL is structurally similar to PRL and GH, but no
specific PL receptor has been found. A recent report
suggests a novel mechanism of PL action in which PL
functionally binds to both the PRLR and GHR in a
heterodimeric arrangement such that GHR is engaged
by the PL site 1 and PRLR is engaged by PL site 2
(Herman et al., 2000). If validated, this would be the
first such heterodimeric interaction reported for
members of the subfamily of cytokine receptors that
includes GHR and PRLR.
Depending on the species of origin of the hormone
and receptor, GH itself may not bind to the GHR.
Primate GHRs cannot bind and be activated by
nonprimate GH. Yet, primate GH (hGH, for
example) can bind and activate both primate and
nonprimate GHRs. The specificity for this longappreciated peculiarity of species-dependent GH±
GHR interaction is now known to reside in
differences in interacting residues contributed from
both GH (residue 171 is Asp in primates and His in
nonprimates) and GHR (residue 43 is Arg in primates
and Leu in nonprimates). Mutagenesis experiments
(summarized in Behncken and Waters, 1999) suggest
that charge repulsion and steric hindrance explain the
species specificity. Leucine at residue 43 of the
nonprimate GHR, being shorter and without charge
compared with arginine, can apparently accept either
Asp171 or His171 from the GH of either primate or
nonprimate, but no such tolerance apparently exists
in the primate GHR arginine at residue 43.
Cell types and tissues
expressing the receptor
When assessed using sensitive RT/PCR methods,
GHR mRNA in humans is widely distributed in
various tissues, including liver, fat, muscle, kidney,
Growth Hormone Receptor 7
Figure 4 High GH concentrations and GH antagonists inhibit GH signaling. (A) Potential
mechanisms of suppression of signaling by high concentrations of GH and the GH antagonist effect.
Unliganded GHR, shown as a monomer, is dimerized in response to GH (upper panel). High-dose
suppression (see bell-shaped dose response curve in B) for GH (middle panel) is envisioned as a
reflection of GH binding to all available GHR molecules via site 1 in unproductive monomeric
interactions. GH antagonist inhibition of GH signaling is viewed as the antagonist (mutated at site 2)
competing for GHR binding via site 1, thus lessening productive GH-induced GHR dimerization. (This
may not explain all aspects of GH antagonist effects.) (B) Concentration-dependence curves for GH
alone and for GH plus GH antagonist treatment of GHR-expressing cells. At very high GH
concentration, several biological and biochemical responses (e.g. proliferation, tyrosine phosphorylation, receptor disulfide linkage) are lessened. Addition of GH antagonist (mutant GH with markedly
decreased site 2 binding affinity) in the presence of constant GH concentration causes inhibition of GH
signaling. A and B are adapted from Frank (2002) with permission.
GH
1 2
A
Active Dimer
GH
1 2
H]
ow
[G
Signaling
L
GH
1 2
GH
1 2
GH
1 2
GH
2 1
No Active Dimer
High [GH]
No Signaling
GH
1 2
+
GHA
1
GH
1 2
GH Low
an [GH
ta
go ]
nis
t
GHA
1
No Active Dimer
No Signaling
B
% Maximal Response
100
Increasing
[GH]
alone
Increasing [GH]
50
0
Antagonist
added
Constant [GH]
plus increasing
[antagonist]
Hormone Concentration
8
Stuart J. Frank and Joseph L. Messina
heart, prostate, fibroblasts, and lymphocytes (Martini
et al., 1995; Hermansson et al., 1997; Ballesteros et al.,
2000). The highest levels are found in liver, followed
by fat and muscle. The truncated GHR isoforms
(lacking most of the cytoplasmic domain) are also
widely expressed, again most abundant in liver, fat,
and muscle, though at much lower levels than the fulllength receptor. GHR mRNA is similarly distributed
in rodent tissues. Among lymphoid cells, assessment
in humans of GHR mRNA abundance as well as flow
cytometry suggest that B cells are much more
enriched in GHRs than are T cells (Badolato et al.,
1994; Rapaport et al., 1995; Hattori et al., 2001).
Although GHR is widely expressed in tissues,
experimentally useful cell lines expressing GHR are
scarce. Some important examples of lines expressing
sufficient GHR to allow biochemical and functional
studies include the human IM-9 B lymphocyte, 3T3F442A and 3T3-L1 mouse pre-adipocyte fibroblasts
and adipocytes, C2C12 rat myoblasts and myotubes,
human HuH7 hepatoma cells, CWSV-1 rat hepatocytes, and H4IIE rat hepatoma cells.
Regulation of receptor expression
In principle, GHR abundance may be regulated by
various mechanisms, including transcriptional, posttranscriptional, and posttranslational mechanisms.
Many studies have examined the hormonal and ontogenic regulation of GHR gene expression at various
target tissues in different species; some have produced
conflicting results. Several excellent reviews that
summarize much of this information include those by
Schwartzbauer and Menon (1998) and Waters (1999).
Release of soluble receptors
GHBP is a high-affinity soluble GH-binding protein
present in the circulation of many species (reviewed in
Baumann, 2001). Roughly 50% of circulating GH in
humans is complexed to GHBP (Baumann et al.,
1988), which is composed of a soluble form of the
GHR extracellular domain. GHBP is derived by two
quite independent mechanisms (see Figure 5). As
Figure 5 Mechanisms of GHBP generation. As described in the text, GH-binding protein (GHBP) is a
circulating version of the extracellular domain of the GHR. In rodents (A), GHBP derives by
alternative splicing of the GHR mRNA, such that a hydrophilic stretch of amino acids (black ball)
replaces the transmembrane and cytoplasmic domains. In humans, rabbits, and other species (B),
GHBP arises by proteolytic cleavage of the membrane GHR in the extracellular juxtamembrane region
to yield the shed GHBP and the GHR remnant. Current evidence favors the transmembrane ADAM
metalloprotease, TACE, as the enzyme catalyzing the GHR proteolysis and GHBP shedding.
GH
1 2
A. Alternative Splicing (rodents)
GHBP
GHR mRNA
Translation
Alternative
Splicing
GH
1 2
GHR
GHR gene
GHBP mRNA
B. Proteolysis (rabbits and humans)
GH
1 2
GHBP
Metalloprotease
Activator
GHR Proteolysis
and
(eg., PMA, PDGF)
GHBP shedding
ADAM
metalloprotease
GHR
GHR Remnant
GH
1 2
Growth Hormone Receptor 9
detailed above, in rodents and some other species,
GHBP is generated by alternative splicing of the
GHR mRNA such that the transmembrane and
cytoplasmic domains are replaced by a short hydrophilic tail that confers secretion. In contrast, GHBP
in human and rabbit is generated by regulated
proteolysis of the full-length GHR and `shedding' of
the extracellular domain as the GHBP. Recent data
indicate that this proteolytic GHR processing is
inducibly mediated by metalloprotease activity, likely
TACE (TNF-cleaving enzyme). Interestingly,
rodent GHRs can also be a target of this activity
(Alele et al., 1998; Zhang et al., 2000; Guan et al.,
2001). In addition to generating GHBP, inducible
GHR proteolysis causes GHR loss and accumulation
of a transmembrane/cytoplasmic domain remnant
and can impact GH action. Cells are desensitized to
GH stimulation after proteolysis is induced; conversely, GH-induced GHR dimerization lessens the
receptor's susceptibility to proteolysis (Zhang et al.,
2001; Frank, 2001).
Aside from these effects of proteolysis on cellular
GH sensitivity, GHBP's role(s) in GH physiology is
not yet clearly known; in different model systems
GHBP can both potentiate and inhibit GH action
(reviewed in Baumann, 2001). In contrast to the cell
surface 1 : 2 GH : GHR stoichiometry, most GHBPassociated GH in human circulation exists in 1 : 1
GH : GHBP stoichiometry. This and slightly higher
affinity association of GH to GHR relative to GH±
GHBP interaction have led to speculation that part of
GHBP's role is as a reservoir for GH, effectively
delivering it from circulation to cell surface GHR
(Baumann et al., 1994). In circulation, GHBP-bound
GH has a prolonged half-life relative to free GH,
likely due to diminished access to GH degradation/
disposal sites within the body (Clark et al., 1996).
Given the pulsatile delivery of GH into the
circulation, one possible role for GHBP is to stabilize
GH bioavailability (Veldhuis et al., 1993).
GHBP levels vary during ontogeny and with
various physiological and pathophysiological states
and it may be that they reflect GHR levels in relevant
target tissues. In humans, GHBP levels rise steadily
during childhood, they vary little diurnally or after
early adulthood, except for decline after age 60
(Silbergeld et al., 1989; Maheshwari et al., 1996).
Children with idiopathic short stature (decreased
height unaccounted for by genetic potential or GH or
other hormonal deficiency) have lower GHBP levels
than controls (Carlsson et al., 1994) perhaps reflecting
a mild GH resistance state. In full-blown GH
insensitivity (Laron) syndrome, both GHR and
GHBP levels are usually very low. GHBP is low in
type 1 diabetes and increased by insulin treatment
(Menon et al., 1992). GHBP is low in malnutrition,
but not in obesity (Hochberg et al., 1992). The role, if
any, of GHBP in these situations is as yet unclear.
SIGNAL TRANSDUCTION
Associated or intrinsic kinases
Carter-Su and colleagues (Foster et al., 1988; CarterSu et al., 1989) were the first investigators to
demonstrate that GH activates intracellular tyrosine
phosphorylation and that a tyrosine kinase activity
copurifies with the GHR. Yet, the GHR lacks an
intrinsic kinase domain (Leung et al., 1987). Like
other cytokine receptors, the GHR was found to
physically and functionally associate with a member
of the Janus tyrosine kinase family, JAK2
(Argetsinger et al., 1993). The JAKs are nonreceptor
cytoplasmic tyrosine kinases that in mammals include
JAK1, JAK2, JAK3, and TYK2 (reviewed in Ihle,
1995). All but JAK3 are ubiquitously expressed;
JAK3 is expressed in a lymphoid-specific fashion. The
JAK family members each have a characteristic
structural organization typified by the presence of a
C-terminal kinase domain, a kinase-like (pseudokinase) domain just N-terminal to the kinase domain,
and the N-terminal one-half of the molecule. JAK2
associates with a number of cytokine receptors,
including the PRLR, EpoR, and thrombopoietin
receptor. Though association with JAK1 has also
been shown, it is thought that GHR's physical
association with JAK2 is critical to GH action.
The GHR's proline-rich Box 1 region, which is
similar to that found in some other cytokine
receptors, is critical in allowing physical and
functional association with JAK2, though full
association may also depend on other membraneproximal receptor cytoplasmic domain regions
(Frank et al., 1994; Sotiropoulos et al., 1994;
VanderKuur et al., 1994). The JAK2 region required
for interaction with the GHR maps to the N-terminal
one-fifth of the molecule, though detailed mapping
within this region is still lacking (Frank et al., 1995;
Tanner et al., 1995). Removal of the JAK2 tyrosine
kinase domain, while it does not support GH-induced
signaling, does not impair association with the GHR,
consistent with the notion that association of the
GHR with JAK2 is not dependent on GH and does
not require tyrosine phosphorylation of either the
receptor or the kinase (Frank et al., 1995). However,
the GHR±JAK2 association is likely enhanced by
GH treatment (Argetsinger et al., 1993) and this
enhanced association appears to depend on GH's
10 Stuart J. Frank and Joseph L. Messina
ability to cause GHR dimerization (Zhang et al.,
1999). Whether dimerization alone or an additional
conformational change in the receptor is required for
optimal JAK2 activation is still unknown (reviewed in
Frank, 2002).
Other tyrosine kinases are activated in response to
GH. These include focal adhesion kinase (FAK) (Zhu
et al., 1998a) and the Src family kinases c-src and
c-fyn (Zhu et al., 1998b). For FAK, there is evidence
that its interaction with the GHR±JAK2 complex
may be via JAK2, though the regions of each
responsible for the interaction have not been defined.
A direct association of the Src family kinases with
GHR or JAK2 has not been observed, but their
involvement in a GH-induced signaling complex via
association with FAK has been speculated.
Additionally, a CORT (cloning of receptor targets)
strategy using the tyrosine phosphorylated distal tail
of the GHR cytoplasmic domain as bait found that csrc kinase (Csk), a tyrosine kinase that negatively
regulates src by tyrosine phosphorylation, can
associate with the tyrosine phosphorylated GHR
(Moutoussamy et al., 1998). This may suggest a
further link of the Src family kinases with the GHR.
Potential roles of these non-JAK2 tyrosine kinases in
GH action are mentioned below.
Cytoplasmic signaling cascades
GH-induced GHR dimerization is presumed to be
critical for GH signaling by promoting the apposition
of JAK2 molecules that are associated with the
dimerized GHRs. In this model, the closely situated
JAK2 tyrosine kinase domains more readily undergo
trans- and autophosphorylation, the net effect of
which is to further enhance JAK2 activation. Though
elements of this model are undoubtedly correct, our
lack of structural information about the GHR
cytoplasmic domain associated with JAK2 makes us
unable to be certain about the actual JAK2 activation
mechanism. In any case, several cytoplasmic signaling
pathways become activated in response to GHinduced tyrosine kinase activation (see Figure 6). For
a more comprehensive discussion of these pathways
and their relevance, the reader is directed to several
recent review articles (Carter-Su et al., 1996; Frank
and O'Shea, 1999; Zhu et al., 2001).
Like signaling through other cytokine receptors,
GHR engagement results in activation of STATs
(signal transducers and activators of transcription).
STATs are latent cytoplasmic transcription factors
that contain an SH2 domain, a principal tyrosine
phosphorylation site, and DNA-binding and transactivation domains. The general model for their
activation by different cytokine receptor±JAK complexes is that the STAT molecule is recruited to the
tyrosine phosphorylated receptor or JAK via the
STAT's SH2 domain, becomes tyrosine phosphorylated by the JAK, and then homo- or heterodimerizes
with another STAT and migrates to the nucleus.
There the STAT dimer exerts transcriptional activation to a target gene that has in its 50 regulatory
region particular DNA sequences specifically recognized by the STATs. Extensive discussion of
mechanisms and consequences of STAT activation
can be found in several excellent recent reviews that
specifically deal with GH-induced STAT signaling
(Davey et al., 1999a; Choi and Waxman, 2000;
Herington et al., 2000). GH promotes the tyrosine
phosphorylation and DNA-binding capacity of
four different STAT molecules ± STAT1, STAT3,
STAT5a, and STAT5b (Campbell et al., 1995;
Gronowski and Rotwein, 1994; Gronowski et al.,
1995; Ram et al., 1996; Silva et al., 1996; Smit et al.,
1997; Waxman et al., 1995).
Though binding sites in the GHR±JAK2 complex
have not been identified for all of these, it is generally
accepted that GH-induced STAT1 and STAT3
activation require little more of the GHR cytoplasmic
domain than the proximal region necessary for JAK2
activation. This is in contrast to activation of
STAT5a and STAT5b, which require GH-induced
tyrosine phosphorylation of the receptor tail in order
to become fully activated with regard to tyrosine
phosphorylation, DNA binding, and transactivation
of target genes (Hansen et al., 1996; Smit et al., 1996,
1997; Sotiropoulos et al., 1995, 1996; Wang et al.,
1996; Yi et al., 1996). In fact, the phosphorylation of
each of certain tyrosine residues in the receptor
cytoplasmic domain has been shown sufficient to bind
and activate STAT5 and STAT5-dependent transactivation. These include the equivalents to human
tyrosines 516, 548, and 609 (Hansen et al., 1996, 1997;
Smit et al., 1996, 1997). It is possible, though not
yet shown, that motifs mediating association with
and activation of STATs 1 and 3 might reside in
JAK2, rather than the GHR. The consequences of
GH-induced STAT activation are discussed below.
Other pathways activated by GH also require
JAK2 activation. These include the MAP kinase
(ERK and JNK) cascades and the PI-3 kinase
cascade; a number of adapter proteins, including
IRS family members, SIRP, and SH2B- are also
recruited in response to GH (Souza et al., 1994;
Ridderstrale et al., 1995; Argetsinger et al., 1995,
1996; Yamauchi et al., 1998; Kim et al., 1998; Stofega
et al., 1998; Carter-Su et al., 2000). GH-induced
ERK1 and ERK2 activation were first shown in 1992
(Anderson, 1992; Campbell et al., 1992; Moller et al.,
Growth Hormone Receptor
11
Figure 6 GHR signaling pathways. As mentioned in the text and detailed in the review articles cited,
the major signaling pathways engaged downstream of the activated GHR±JAK2 assembly include the
STAT, ERK, and PI-3 kinase pathways. Some cascades leading to their activation and crosstalk
between them are indicated. Tyrosine phosphorylation is indicated by Yp. Serine/threonine
phosphorylation is indicated by S/Tp. Crosstalk between the GHR and the EGFR±ErbB2 system is
shown with GH causing tyrosine phosphorylation of the EGFR and serine/threonine phosphorylation
of ErbB-2. The former is believed to contribute to GH-induced ERK activation; the latter is thought
to desensitize ErbB-2 to EGF-induced activation. Some downstream biological and biochemical
outcomes of activation of these pathways are indicated in the shaded boxes. Other pathways activated
and referred to in the text are in the open box.
1
EGF
GH
2
GHR
EGFR
ErbB2
EGFR
2
JAK
Yp
Yp
Plasma
Membrane
Yp
IRS 2/3
Yp
Yp
S/Tp
Shc
Grb2
Sos
–
JAK2
IRS 1
–
PI3K
SHP2/SIRP
+
Ras
STAT1/3
Raf
Other
Pathways
(src
kinases,
p38, JNK,
SH2B)
MEK
ERK
STAT5
Proliferation
c-fos
Proliferation
1992; Winston and Bertics, 1992). GHR's ability to
couple to ERK activation corresponds to its ability to
effectively couple to a catalytically active JAK2
molecule ± only the membrane proximal GHR region
is required for this pathway (Moller et al., 1992;
Sotiropoulos et al., 1994; VanderKuur et al., 1994;
Frank et al., 1995). Several potential upstream
activators of the ERK pathway are accessed by GH.
GH activates the Shc±Grb2±Sos±Ras±Raf pathway
with kinetics that suggest it is a mechanism of ERK
activation (VanderKuur et al., 1995, 1997). It has also
been observed that GH-induced ERK activation can
be inhibited by PI-3 kinase inhibitors and that
expression of IRS-1 in IRS-deficient cells enhances
GH-induced ERK activation in a PI-3 kinase
inhibitor-sensitive fashion, findings that suggest that
the PI-3 kinase pathway (or a related enzyme
pathway) may function upstream of ERK activation
anti-apoptosis
? IGF-1
Spi 2.1
ALS
Insulin
CYP genes
SOCS genes
IGF-1
(Kilgour et al., 1996; Hodge et al., 1998; Liang et al.,
2000). GH-induced activation of the SHP-2 protein
tyrosine phosphatase may also positively modulate
ERK activation (Kim et al., 1998).
Another interesting route to GH-induced ERK
activation is JAK2-mediated tyrosine phosphorylation of the epidermal growth factor receptor (EGFR).
Yamauchi et al. (1997) showed that GH-induced
phosphorylation of EGFR, likely at residue Y1068,
allowed Grb-2 association at that site and augmented
GH-induced ERK activation. This was unaccompanied by a change in EGFR kinase activity, implying
that GH-induced ERK signaling was utilizing EGFR
as an adapter molecule.
As yet, the relevance of MAP kinase and PI-3
kinase activation by GH is not certain and may differ
widely, depending on the cell type in question. A role
in GH-induced proliferation in some cells is possible,
12 Stuart J. Frank and Joseph L. Messina
as expression of IRS-1 in IRS-deficient 32D cells
enhances GH-stimulated proliferation (Liang et al.,
1999). Some reports suggest an anti-apoptotic effect
of GH, which may relate to the PI-3 kinase/Akt or
NFB pathways (Costoya et al., 1999; Jeay et al.,
2000, 2001). Yet, in some cells, such as 3T3-F442A
fibroblasts, GH inhibits proliferation induced by
epidermal growth factor. In those cells, GH also
causes a desensitization of EGF-induced activation of
the EGFR family member ErbB-2, and this desensitization is mediated by ERK activation (Kim et al.,
1999). Independent of its role in proliferation, ERK
activation has clearly been related to c-fos activation
that is acutely stimulated by GH (Hodge et al., 1998)
and full activation of GH-induced STAT5 signaling
may also rely on ERK activation (Pircher et al.,
1999). Further, other MAP kinases, including JNK
and p38, have been shown in some systems to be
activated in response to GH and p38 may allow
mitogenesis, as well as cytoskeletal reorganization
(Zhu et al., 1998b; Goh et al., 2000; Zhu and Lobie,
2000).
GH-activated signaling is modulated by several
molecules. SH2-B has been shown to be a JAK2
activator; its association with JAK2 may augment
signaling (Carter-Su and Rui, 1999). The SOCS
proteins are activated in response to GH and
negatively regulate in several ways via interactions
with both GHR and JAK2 (Ram and Waxman,
1999). Other signaling molecules, such as SIRP and
Grb-10, may also attenuate GH signaling
(Moutoussamy et al., 1998; Stofega et al., 2000).
These are in addition to the homologous downregulation of GH signaling mediated by receptor
ubiquitination,
endocytosis,
and
degradation
(reviewed in Frank, 2001).
DOWNSTREAM GENE
ACTIVATION
Transcription factors activated
GH activates a number of transcription factors
(see Table 1). The STATs were mentioned above.
STATs 1, 3, 5a, and 5b are activated in a number of
systems by GH. In both humans (Winer et al., 1990;
Pincus et al., 1996; Veldhuis, 1996) and, more
dramatically in rodents (Jansson et al., 1985), GH
secretion and therefore GH levels are pulsatile in a
sex-specific manner. That is, in males GH pulses
occur at roughly 3.5 hour intervals with interpulse
levels being nearly undetectable (Tannenbaum and
Martin, 1976). In females, the pulses are dampened
and there are nearly continuous GH levels. Of the
STATs, only STAT5b transcriptional activation
responds to this pulsatile GH secretion. In liver and
liver cell culture models, STAT5b is activated by a
GH pulse, after which it is deactivated and
restored for activation by the time a second pulse is
given 4 hours later. Constant GH treatment
Table 1 GHR target genes, transcription factors, and relevant effects
Target gene
Transcription factor/pathway
Effect relevant to GH action
IGF-I
?HNF-1, STAT5b, ?PI-3 kinase pathway
Growth mediation
c-fos
ERK pathway, TCF, SRF, STATs 1, 3
Acid labile subunit (ALS) of
IGFBP-3 complex
STAT5b
Serine protease inhibitor 2.1
STAT5b
SOCS 1,2,3,CIS
STAT5b
Negative regulation of
GHR/JAK2 activation
CYP2C11
STAT5b
Male-specific hepatic expression
CYP2C12
STAT5b
Female-specific hepatic expression
Egr-1
ERK pathway, TCF
Jun-B
ERK pathway, TCF
ATF-2, CHOP, p38 MAPK pathway
IGF-binding protein
Mitogenesis
Some target genes affected by the activated GHR, the pathways and/or transcription factors believed to influence them, and relevant GH
action effects (if known) are listed. See text for details.
Growth Hormone Receptor
(mimicking more the female pattern) leads to a lower
level, less pulsatile STAT5b activation profile
(reviewed in Choi and Waxman, 2000; Schwartz,
2001). This pattern leads to sexually dimorphic
expression of certain GH-dependent genes in liver
(more below).
Other transcription factors whose functions are
affected by GH include the list in Table 1. It is a list
that has grown significantly in recent years and
includes such proteins as the ternary complex factor
(p62TCF/Elk1), serum response factor (SRF),
CCAAT/enhancer-binding protein (C/EBP), C/
EBP, C/EBP homologous protein (CHOP), activating transcription factor 2 (ATF-2), yin yang 1 (YY1),
hepatocyte nuclear factor 1 (HNF-1), HNF-4, and
the glucocorticoid receptor (Liao et al., 1997, 1999;
Hodge et al., 1998; Meton et al., 1999; Bergad et al.,
2000; Lahuna et al., 2000; Zhu and Lobie, 2000;
Piwien-Pilipuk et al., 2001).
Genes induced
A number of genes have been shown to be activated
by GH (Table 1), though the signaling pathways
and transcription factors involved are not completely understood for each. GH's induction of the
insulin-like growth factor I (IGF-I) gene was
among the earliest appreciated and is biologically
relevant (see below) (Doglio et al., 1987; Bichell
et al., 1992). Transcription factors implicated only
recently in GH-induced IGF-I expression include
HNF-1 and STAT5 (Meton et al., 1999; Davey et
al., 2001). However, pathways involved may differ
between cell types, since PI-3 kinase inhibitors have
been shown to either inhibit or potentiate GHinduced IGF-I transcription in hepatocytes versus
myotubes, respectively (Shoba et al., 2001; Sadowski
et al., 2001).
Other genes thought important in GH action that
are regulated at least in part by STAT5 include: the
suppressors of cytokine signaling (SOCS) proteins
SOCS-1, -2, -3, and CIS in liver (Adams et al., 1998;
Davey et al., 1999b; Ram and Waxman, 1999; TolletEgnell et al., 1999); serine protease inhibitor (Spi) 2.1
(LeCam et al., 1987; Bergad et al., 1995); acid labile
subunit (ALS) of the IGFBP-3 complex (Ooi et al.,
1997); insulin (in rat insulinoma cells) (Galsgaard
et al., 1996); and a number of hepatic cytochrome
P450 (CYP) genes involved in the metabolism of
endogenous steroids (Waxman, 1992; Waxman et al.,
1995). For some in this latter group, the sexually
dimorphic pulsatile GH secretion dictates a
13
STAT5b-mediated sexually dimorphic expression
(reviewed in Choi and Waxman, 2000) (more
below). GH-activated c-fos gene expression is
mediated in part by the STAT1/3 and ERK1/2
pathways (Hodge et al., 1998; reviewed in Herington
et al., 2000).
Promoter regions involved
In genes such as Spi2.1 and the acid labile subunit,
STAT5, when activated in response to GH, binds to
a DNA enhancer sequence called a gamma-activated
sequence (GAS)-like element (GLE) (Bergad et al.,
1995; Ooi et al., 1998). The GLE consensus sequence is 50 -TTC-NNN-GAA-30 (Seidel et al., 1995).
In these genes, STAT5 can synergistically bind to
two adjacent GLEs such that two STAT5 dimers
interact with the enhancer, effecting transcriptional
activation. In other GH-regulated genes that may be
in part influenced by STAT5 activation, such as the
IGF-I gene, the promoter element(s) involved are
much less clear. For the IGF-I gene, the issue of
deciphering its regulatory elements is difficult both
because of the gene's complexity and the relative
lack of GH-responsive cell lines for study of IGF-I
gene expression. To date, the major findings
include the presence of a DNase1 hypersensitivity
site within a 350 bp region of exon 2 of the rat
IGF-I gene (Thomas et al., 1995) and the demonstration in GHR-transfected rat C6 glioma cells of
GH-responsiveness of a luciferase gene driven by a
5.5 kb fragment of the rat IGF-I gene that included
412 bp of 50 flanking sequence of exon 1, exon 1,
intron 1, exon 2, intron 2, and a fragment of exon 3
(Benbassat et al., 1999). There are, as yet, no clear
consensus sites for transcription factor binding
identified in this gene as indicative of its GH
regulation.
STAT1 and STAT3 are involved in GH regulation
of the c-fos gene. GH treatment of tissue culture cells
causes binding of homo- and heterodimers of
STATs 1 and 3 to the c-sis-inducible element (SIE)
of the c-fos promoter (Campbell et al., 1995;
Gronowski and Rotwein, 1994; Meyer et al., 1994;
Ram et al., 1996). Other regions of the c-fos enhancer
are involved in GH-mediated transactivation in an
apparently STAT-independent fashion. Both SRF
and TCF/Elk-1 inducibly bind to the c-fos serum
response element (SRE) and contribute to induction
of c-fos transcription in response to GH in an ERK
pathway-dependent fashion (Hodge et al., 1998;
Meyer et al., 1993).
14 Stuart J. Frank and Joseph L. Messina
BIOLOGICAL CONSEQUENCES
OF ACTIVATING OR INHIBITING
RECEPTOR AND
PATHOPHYSIOLOGY
Phenotypes of receptor knockouts
and receptor overexpression mice
Table 2 summarizes the phenotypes of mice with
knockout of some molecules relevant in GHR
function. The GHR global knockout (GHR / )
mouse was described in 1997 (Zhou et al., 1997).
No tissue-specific knockouts have as yet been
reported. As expected, the GHR / animal also had
no circulating GHBP. Because its phenotype
strongly resembled that of the human syndrome of
GH resistance described by Laron (more below),
this mouse is also referred to as the Laron mouse.
The most striking features initially observed
included postnatal growth retardation in both males
and females, markedly reduced serum IGF-I levels,
and elevation of serum GH concentration. More
studies with these mice have recently uncovered
interesting features, only some of which may
mimic the human disorder. Reduced bone growth in
GHR / mice was shown to be due to reduced
chondrocyte proliferation and cortical bone growth
postnatally and bone turnover was also reduced; these
effects were rescued with IGF-I treatment (Sims et al.,
2000).
In addition, defects in both male and female
reproductive function have been observed in these
mice (Danilovich et al., 1999; Chandrashekar et al.,
2001). Interestingly, a potentially clinically relevant
observation with these mice is that they are protected
against the development of diabetic nephropathy,
suggesting a role for GH in mediating this pathology
(more below) (Bellush et al., 2000). In contrast to
humans, a striking characteristic of Laron mice is that
they live significantly longer than their GHR+/+ or
GHR+/ littermates, though the reasons for this are
not yet known (Coschigano et al., 2000).
Targeted disruption of other important molecules
implicated as mediators of GH action have recently
been reported to yield phenotypes in some ways
similar to the Laron mouse. Unrestricted STAT5b
knockout was reported in 1997 (Udy et al., 1997).
STAT5b / mice exhibit poor postnatal growth,
abnormal adipose tissue development, and a loss of
the sexually dimorphic hepatic expression of several
GH-responsive genes. Further, they have low IGF-I
concentrations in the serum without low GH levels;
thus, it is thought that STAT5b deficiency renders the
animals GH pulse-resistant and that STAT5b may
mediate GH-induced IGF-I gene expression (Udy
et al., 1997; Davey et al., 2001). Interestingly, deletion
of the HNF-1 gene also leads to postnatal growth
retardation, low IGF-I levels, and elevated GH (Lee
et al., 1998) and HNF-1 has been implicated in GHinduced IGF-I gene expression (Meton et al., 1999).
Though some of these data appear to favor GHinduced liver-derived IGF-I as a prime mediator of
GH's somatogenic effects, it is informative to
consider the recently described unrestricted and
liver-specific IGF-I knockout mice (reviewed in
LeRoith et al., 2001). Liver-specific IGF-I knockout
resulted in a substantial lowering of circulating IGF-I
and a raised GH level, but, surprisingly, no effect on
body growth. Unrestricted IGF-I knockout, in those
animals that survived, did yield significant growth
retardation. Thus, while GH promotes both hepatic
and peripheral IGF-I release, much of its growth
effects may derive from autocrine/paracrine action of
IGF-I produced extrahepatically. Tissue-specific
GHR knockout studies may yield further insights
into these issues.
Table 2 Phenotypes of mice with knockout of molecules important in GH action
Gene knockout
Phenotypic features
GHR
Postnatal growth retardation, low IGF-I level, elevated GH level,
bone growth and reproductive abnormalities
JAK2
Embryonic lethality, defective hematopoiesis
STAT5b
Postnatal growth retardation, low IGF-I level, loss of sexually
dimorphic hepatic expression of several GH-responsive genes
HNF-1
Postnatal growth retardation, low IGF-I level, elevated GH level
IGF-I
Unrestricted ± variable perinatal lethality, pre- and postnatal growth
retardation, other abnormalities
Liver-specific ± normal growth, low IGF-I level, elevated GH level
Growth Hormone Receptor
Human abnormalities
The effects of both excessive and diminished GH
action are clinically seen in humans. Pituitary tumors
that secrete excessive GH cause the syndrome of
acromegaly, with connective tissue and bony overgrowth, visceromegaly, insulin resistance, and, if
occurring prior to epiphyseal closure, excessive height
(Ben-Shlomo and Melmed, 2001). Diminished GH
action is most commonly caused by decreased
pituitary GH secretion, but can also be seen in the
GH resistance (Laron) syndrome. Laron described
the index cases in the 1960s (reviewed in Laron, 1995)
± children with severe growth retardation, low IGF-I
levels, and elevated circulating GH concentrations.
Other features exhibited by Laron syndrome patients
include obesity, small gonads and genitalia, and
acromicria.
A range of different GHR mutations that underlie
this syndrome in kindreds worldwide have been
described (reviewed in Parks et al., 1997). These may
impair GHR gene expression, proper GHR cell
surface expression, GH binding, or possibly GH
signaling. In most cases, Laron syndrome patients
lack circulating GHBP (presumably because of a lack
of surface GHR to undergo shedding), but in some
GHBP is present (or even increased), depending on
the mutation. It is not yet clear whether more subtle
GHR mutations may lead to the syndrome of
idiopathic short stature (Goddard et al., 1995;
Sanchez et al., 1998).
THERAPEUTIC UTILITY
Effect of treatment with soluble
receptor domain
To date, we are not aware of any clinical utilization of
the GHR soluble extracellular domain (GHBP) in
humans. In animal and in vitro experimentation,
recombinant GHBP has had varying effects, as
alluded to above. Coadministration of GH and
recombinant GHBP to GH-deficient rodents, for
instance, enhances GH's growth-promotion (Clark
et al., 1996). Yet, when applied to GH-responsive cell
lines, GHBP inhibits GH binding and GH-induced
biological responses, likely by sequestering GH from
cell surface GHR or forming inactive GH±GHBP±
GHR complexes rather than GH±GHR dimer
complexes (Lim et al., 1990; Mannor et al., 1991;
Hansen et al., 1993). Thus, the net effect of GHBP
treatment is as yet unclear.
15
Effect of inhibitors (antibodies)
to receptors
There have not been trials of anti-GHR antibodies for
clinical purposes. Mutant recombinant GH molecules
that are altered so as to markedly diminish site 2
binding affinity have been developed, however
(reviewed in Kopchick and Okada, 2001) (see dashed
line, Figure 4B). These molecules are unable to cause
proper GHR dimerization and are therefore ineffective for promoting GH signaling. In addition, in
particular when a double mutant is engineered that
combines enhanced site 1 affinity with decreased site 2
affinity, this molecule acts as an antagonist of
endogenous (normal) GH action, presumably by
lessening the availability of GHRs for productive
GH-induced dimerization. Recently a PEG (polyethylene glycol)-ylated version of such an antagonist
(which, by virtue of PEGylation has a long circulating
half-life) has been shown to be effective in treating the
syndrome of acromegaly (reviewed in Drake et al.,
2001).
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