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GRH-SOMATOSTATIN-GH |
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, Birmingham, Alabama 35294
Address all correspondence and requests for reprints to: Stuart J. Frank, University of Alabama at Birmingham, 1530 Third Avenue South, BDB 861, Birmingham, Alabama 35294-0012. E-mail: frank{at}endo.dom.uab.edu
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Abstract |
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 Top Abstract IntroductionGeneral Aspects of GH...GHR and EpoR...Concluding RemarksReferences |
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Introduction |
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TopAbstractIntroductionGeneral Aspects of GH...GHR and EpoR...Concluding RemarksReferences |
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General Aspects of GH and Epo Action and Signaling |
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TopAbstractIntroductionGeneral Aspects of GH...GHR and EpoR...Concluding RemarksReferences |
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While each of the cytokine receptor family members are cell
surface-expressed transmembrane proteins with extracellular domains
that often participate in ligand binding, many of them appear to
function only when part of a heterooligomeric assemblage. Some can even
function as a subunit of receptors for more than one cytokine
(13). For example, the common 
chain is an important
component of the receptor complexes for several different ILs
(including IL-2, -4, -7, -9, and -15), whereas the common ß chain
partners with at least three different 
chains to form the distinct
receptors for IL-3, IL-5, and granulocyte-macrophage colony stimulating
factor. The GHR and EpoR, unlike these other family members, are each
believed to alone (as homodimers in their active signaling
conformations) bind their cognate ligands to initiate intracellular
signaling. For this reason and because of their particular structural
similarities, GHR and EpoR (along with the PRL and thrombopoietin
receptors) form a subgroup among the larger group of over twenty Class
I cytokine receptors.
Unlike tyrosine kinase growth factor receptors (such as the insulin, IGF-1, and epidermal growth factor receptors) neither GHR nor EpoR encodes enzymatic activity in their cytoplasmic domain. Rather, cytokine receptors physically and functionally couple variably to nonreceptor tyrosine kinases of the Janus family, which includes JAK1, JAK2, JAK3, and TYK2 (13, 14). These proteins are each characterized by the presence of a C-terminal tyrosine kinase domain, an inactive kinase-like (or pseudokinase) domain, and a large N-terminal half believed important for interaction with particular cytokine receptors and other signaling effector and modulator proteins. GHR and EpoR again exhibit similarity in that a wealth of biochemical evidence indicates that both receptors use JAK2 (15, 16, 17). The biological evidence on this point is most clear for EpoR, which unlike the GHR, is itself necessary for in utero development. Targeted disruption of the JAK2 gene results in embryonic lethality due to an absence of red blood cell formation (18, 19).
More detailed attention will be devoted to the activation mechanisms of GHR and EpoR below, but it is important to note that these receptors also share some common activation pathways downstream of JAK2. For example, in comparison to other STATs, both GH and Epo preferentially activate STAT5. However, there may be differences in the degree to which this STAT contributes to GH vs. Epo functions and as to which isoform of STAT5 (A or B) is most relevant for GH and Epo signaling. The STAT5B knockout mouse is small and displays a loss of the normal GH-dependent sexual dimorphism of liver gene expression, suggesting that STAT5B is a particularly important mediator of GH action (20). On the other hand, the STAT5A/B knockout mouse has only a mild anemia (21, 22), suggesting that other pathways may additionally contribute to Epo function. Further, a very recent study examined the effects of reconstitution of mice with EpoR cytoplasmic domain mutants that lacked the tyrosine residues required for STAT5 activation and found again that only a mild anemia resulted (23). It is noteworthy that such reconstitutions of GHR-deficient mice with similarly mutated GHRs have yet to be reported; thus, we do not yet have the full picture of STAT5’s specific biological significance for GH signaling. A number of other pathways known to be important in cell growth, antiapopotosis, and differentiation, such as the MAP kinase and PI3K pathways, are also accessed by both GH and Epo, though we also do not yet know how biologically important are each of these pathways in GH or Epo action.
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GHR and EpoR Dimerization—Similarities and Differences |
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TopAbstractIntroductionGeneral Aspects of GH...GHR and EpoR...Concluding RemarksReferences |
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What might be the nature of these important ligand-induced changes?
An elegant series of investigations to address this question began
with crystallographic and mutagenetic studies of the GH-GHR
interaction in the early 1990s. deVos et al.
(4) bacterially expressed the recombinant human GHR
extracellular domain (amino acids 1–238 of the 246 predicted
extracellular domain residues, referred to as the GH binding protein,
or GHBP) and cocrystallized it with recombinant human GH (see Fig. 1A
). Structurally, the receptor
extracellular domain was found to be divided into two ß sandwich
subdomains, referred to as subdomain 1 (residues 1–123) and subdomain
2 (residues 128–238) with each subdomain comprised of seven ß
strands organized into two antiparallel ß sheets. A four-residue
hinge region links subdomains 1 and 2. Surprisingly, the analysis
yielded a ligand-receptor complex of 1:2 GH:GHBP stoichiometry. This is
particularly intriguing in that GH has no axis of symmetry; yet, two
distinct sites ("site 1" and "site 2") in the GH molecule were
shown to engage the two GHR extracellular domains at similar contact
points on each GHBP. GH contacts the receptor largely at residues in
subdomain 1 and the hinge region. The crystal structure showed that the
tripartite GH-GHBP2 complex is further stabilized
by interaction between the receptor dimer partners via subdomain 2 of
each GHBP in a rather extensive region referred to as the dimerization
interface. This interface includes six intermolecular bonds between
GHBP-I and GHBP-II (serine-145/aspartic acid-152;
leucine-146/serine-201; threonine-147/aspartic acid-152;
histidine-150/asparagine-143; asparagine-152/tyrosine-200;
serine-201/tyrosine-200) and occupies 500 A2, as
compared with roughly 1230 A2 and 900
A2 for the site 1-GHBP and site 2-GHBP
interactions, respectively. This work was important on many levels, not
the least of which is that it represented the first ligand-receptor
complex whose structure was resolved to such a high degree. Further,
though the structure included no information concerning the
transmembrane or cytoplasmic domains, it suggested that the
GH-activated GHR was in a homodimeric assemblage and that perhaps the
cytoplasmic domain-associated JAK2 molecules were thus approximated as
a consequence of GH binding.
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). The prevailing view has favored the idea that GH
promotes GHR dimerization (possibility 2). This is based at least in
part on the finding that various measures of GH action in cell culture
systems exhibit a bell-shaped GH concentration dependence (Fig. 2A). At high GH concentrations, the
responses become dose dependently diminished (27). Binding
studies and mutagenesis of both GH and GHR extracellular domain have
suggested that GH site 1 binding to GHR is of higher affinity than that
of site 2 and that binding is thus sequential with site 1 binding to
one GHR facilitating site 2 binding with the second GHR (27, 28). The bell-shaped dose response is interpreted to indicate
that at very high GH concentration, GH binds to available GHR molecules
via site 1 in unproductive monomeric interactions (Fig. 2B). A
byproduct of the work defining the GHR binding sites 1 and 2 on GH was
the further development of GH antagonists (27, 29, 30, 31, 32).
Site directed mutation of human GH glycine 120 (mouse GH glycine 119)
to arginine or lysine (hGH-G120R or hGH-G120K, respectively) results in
a molecule with markedly reduced site 2 affinity (27, 29, 30, 31, 32, 33). When combined with the G120K alteration, mutations that
enhance site 1 affinity result in a potent antagonist B2036, which,
when PEGylated, has been found efficacious in the treatment of
acromegaly (34, 35).
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). Thus, the functional
findings with GH antagonists could support the view that GH normally
works to promote GHR activation by the sequential dimerization of
previously undimerized GHRs, as above. However, they could equally well
be consistent with the presence of rather loosely associated, yet
dimerized, GHRs in the basal state that become a more avidly associated
dimer in the presence of GH. In part to address this issue, two
independent groups have generated crystal structures of a GH antagonist
bound to the GHBP (37, 38). In both cases, the crystals
revealed a 1:1 stoichiometry of GH antagonist:GHBP with GH antagonist
site 1 mediating the association with the receptor, perhaps favoring
(but not directly testing) the notion that the unliganded GHR is a
monomer. In these structures, the conformation adopted by the bound
receptor did not significantly differ from that of the site 1-bound
GHBP in the case of the wild-type GH:GHBP2
structure. Thus, it was concluded by these investigators that site 2
binding of GH to a second GHR did not induce significant conformational
change in the already (site 1) bound GHR. Yet, the situation as it pertains to the cell surface GHR may prove more complex than that inferred from the crystal structures of the recombinant hormone-GHBP complexes. For example, studies of the effects of treatment of GHR-expressing cells with the GH antagonist have yielded both expected and surprising results. As might be predicted, several groups have observed that treatment of GH-responsive cells with the GH antagonist by itself fails to promote proliferation or tyrosine phosphorylation of the GHR and other cellular proteins and that coaddition of GH antagonist with GH at ratios of 3:1–5:1 inhibits these GH-induced effects (26, 27, 32, 36, 40, 41). But surprisingly, chemical cross-linking studies showed that radiolabeled G120R interacts with cell surface GHRs so as to be in a complex that includes a dimeric GHR (40) in contrast to the crystallographic studies of the antagonist-GHBP interaction. Further, rather than interacting with surface GHRs in a fashion that prevents any aspect of receptor function, two groups have determined that both the G120R and B2036 GH antagonists cause the GHR to internalize with kinetics indistinguishable from those found with wild-type GH treatment (40, 41). These findings suggest that the GH antagonists, though they clearly inhibit the effects of GH and by themselves are not GH agonists, can indeed either cause some degree of GHR dimerization and/or may be interacting in some way with an already-existing GHR dimer (42).
Our own findings add another aspect to the GHR dimerization issue. Using anti-GHR immunoblotting, we have observed in several cell lines that GH induces formation of a covalent GHR dimer detectable only when the receptor is electrophoretically resolved under nonreducing conditions (26, 43, 44, 45). This disulfide-linked GHR form does not appear to result from disulfide exchange following protein extraction and it is abrogated by mutation of cysteine-241 (the only unpaired GHR extracellular cysteine residue). This cysteine is highly conserved among species and is predicted to reside at the GHR juxtamembrane stem. We are as yet uncertain of its role, but our preliminary evidence suggests that the disulfide-linked GHR may be trafficked differently in response to GH than those GHR dimers (roughly one-half by our estimate) that do not undergo this linkage (44 and unpublished results). Independent of its exact function, the disulfide-linked GHR is not formed in response to G120K and G120K antagonizes its formation by GH (26). We currently view the disulfide linkage as a biochemical proxy for "proper" GH-induced GHR dimerization and note that unliganded GHRs are not disulfide linked.
Does GH induce GHR conformational change?
These observations do not yet allow resolution of the issue of
whether the GHR exists as a dimer of some sort before engagement by GH,
but they do suggest that if it is a preformed dimer, GHR likely
undergoes a GH-induced conformational change to achieve the status
required to trigger receptor signaling. Indeed, there is emerging
evidence favoring the possibility of such a conformational change.
Mellado et al. (46) showed that a monoclonal
antibody raised against the GHR extracellular domain and reactive with
the hinge region between subdomains 1 and 2 was capable independent of
GH of promoting GHR-mediated activation of intracellular tyrosine
phosphorylation and cellular proliferation. Moreover, GH (but not
G120R) treatment enhanced the recognition of the GHR epitope by that
antibody. Rowlinson et al. (47) similarly found
that a stimulatory monoclonal antibody that causes GHR dimerization
lost its ability to stimulate when the F'-G' loop of subdomain 2 of the
receptor extracellular domain was mutated. This region of the receptor
was previously implicated by the same group as possibly undergoing a
GH-induced conformational change (48). Collectively, the
findings of these two groups may suggest that a GH-induced
conformational change in the GHR extracellular domain, along with GHR
dimerization, may be needed for optimal receptor activation. One
interesting corollary to this interpretation might be that our observed
GH-induced disulfide linkage of receptors may only be allowed when the
GH-induced conformational change is achieved. Such a possibility is
testable and could yield mechanistically important information about
early steps in GHR activation.
EpoR—a different kind of dimer?
Given the relatedness of the GHR and EpoR in the cytokine receptor
superfamily and the degree to which there are similarities in their
signaling mechanisms, it is worth comparing the two receptors with
regard to the role that dimerization plays in activation. Work in the
early 1990s, before a structural understanding of the GH-GHBP complex,
indicated that a mutant murine EpoR with a change in the extracellular
domain arginine residue 129 to cysteine (R129C) conferred
Epo-independent proliferation in factor-dependent cells
(49). Primary sequence comparison later suggested that
arginine-129 was in a position in the EpoR extracellular domain
analogous to the then recently defined dimerization interface in the
GHR extracellular subdomain 2 in the GH-GHBP2
crystal structure. This result prompted biochemical analysis of the
R129C EpoR mutant and it was found to exist in a constitutive
(Epo-independent) disulfide-linked dimer when expressed in cells
(50).
This finding suggested that EpoR activation, like GHR activation, might normally be mediated by Epo-induced EpoR dimerization of some sort, which was being mimicked in an Epo-independent fashion by the presence of the cysteine-mediated disulfide linkage in the case of the R129C mutant. (Notably, in distinction to our findings in several species that GH induces disulfide linkage of the GHR, Epo-induced EpoR disulfide linkage has not been observed for the wild-type EpoR.) Further evidence for the formation of a Epo:EpoR 1:2 complex akin to that for GH-GHR came from biophysical studies of the interaction of recombinant Epo and EpoR extracellular domain. These studies indicated that two Epo binding sites interacted with EpoR extracellular domain monomers and that the high affinity site (analogous to GH site 1) was of far greater (1000-fold) affinity than that of the low affinity (site 2) site (51). This difference in the affinities of the two Epo sites was substantially greater than that estimated for the analogous GH sites, suggesting that, though similar, there might be important differences in the mechanisms of inducible EpoR vs. GHR dimerization. Along these lines, it is interesting to note that far greater concentrations of Epo relative to GH are apparently required to cause self-antagonism (the bell-shaped concentration dependence) of signaling through the EpoR than are required for GH self-antagonism (52).
In the past several years, more detailed structural information about the Epo-EpoR association has emerged. The first crystal structures of the liganded recombinant EpoR extracellular domain (EBP) probed its interactions with Epo-mimetic and Epo-antagonistic peptides (53, 54). These peptides with structures unrelated to Epo were originally isolated by phage display screening procedures designed to obtain Epo-mimetics (55). In each case, a dimeric ligand (mimetic or antagonist) engaged an EBP dimer, but the orientation between the EBP dimer partners differed in the case of the mimetic- vs. antagonist-bound EBPs. This difference in orientation was interpreted as related to whether the intracellular domains of the EpoR would be brought into productive vs. unproductive signaling orientations. Interestingly, contacts between the EBP dimer partners in both cases were much less extensive than those found in the GHBP dimer in complex with GH.
Owing to difficulty in crystallizing Epo, the Epo-EBP interaction was not studied until late 1998 (56); in fact, this structure could only be obtained by making selected mutations in both Epo and EBP. The Epo mutein, not surprisingly, adopted an overall antiparallel helical bundle configuration similar to GH. The Epo-EBP complex, like the GH-GHBP complex, assumed a 1:2 stoichiometry with "site 1" and "site 2" Epo sites interacting with each EBP. However, in sharp distinction to the GHBP dimer, the EBP dimer found in complex with Epo (like that complexed with the Epo-mimetic and the Epo-antagonist) evidenced a relatively minimal dimerization interface. Interestingly, the only interaction in the EpoR dimerization interface is between the side chains of residues serine-135 and glutamic acid-134 on adjacent EPBs (56), a position in the vicinity of the R129C mutation that confers constitutive activation. Thus, the crystallographic and kinetic analyses of the ligand-engaged EpoR extracellular domain dimerization allow several potentially important distinctions to be drawn between EpoR and GHR dimerization: 1) EpoR displays a markedly lower sensitivity than GHR to high-dose suppression by its ligand; 2) EpoR extracellular domain, unlike GHR, adopts a dimeric conformation even when engaged by a functional Epo-antagonist; 3) the dimerization interface in subdomain 2 of the Epo-engaged EBP is far less extensive than is that of the GH-engaged GHBP, despite the adoption of a 1:2 ligand:BP assemblage by both.
Whether these rather surprising distinctions are meaningful is as yet
uncertain. However, recent structural and mutagenetic studies of the
EpoR over the past 3 yr have produced very interesting results that
should make further comparison with the GHR more compelling. Companion
reports by Livnah et al. and Remy et al. in 1999
(57, 58) yielded important evidence that the EpoR in the
unliganded state exists as a dimer. The crystal structure
shows that the unliganded EBP dimer is in an open-scissors-like
configuration with the dimerization interface consisting of
self-association of the two ligand binding sites on the EBPs and with
the C-terminal end of the subdomain 2 regions of the EBPs being quite
far apart (over 70 Å) (57) (Fig. 3). In the liganded EBP structures, these
C-terminal regions become much closer (30 Å for the Epo-engaged EpoR).
Thus, it is envisioned that the preformed dimer, by keeping the
cytoplasmic domains apart, is in an inactivated state, but ligand
occupancy brings the extracellular and cytoplasmic domains into
proximity and allows signaling. Fragment complementation assays
(58) confirmed these data by demonstrating a dramatic
ligand-induced enhancement of proximity of the cytoplasmic domains of
EpoR dimers. Thus, these studies strongly point to the existence of
preformed EpoR dimers that are activated by a distinct conformational
change in response to ligand.
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Finally, another recent study highlighted the likely structural
importance of the EpoR perimembraneous cytoplasmic domain in
facilitating transmission of the presumed conformational change in the
receptor’s extracellular domain to productive interaction of the
cytoplasmic domain with JAK2. Using a combination of computer modeling
and mutagenesis, Constantinescu et al. (61)
demonstrated that a juxtamembraneous cytoplasmic domain element just
N-terminal to the EpoR Box 1 element contains a hydrophobic motif
necessary for JAK2 activation and receptor signaling. This motif is
likely to be conformationally rigid and -helical. Also, mutations of
critical hydrophobic residues within it abrogate Epo-induced JAK2
activation. However, insertional mutations that alter the register of
the -helix but leave intact the hydrophobic residues, result in
Epo-induced JAK2 activation without EpoR tyrosine phosphorylation or
downstream signaling. Thus, it was proposed that the juxtamembrane/Box
1 region is important in both activation of JAK2 and positioning of the
EpoR cytoplasmic domain in the conformation to be a proper JAK2
substrate. These authors note that this juxtamembraneous motif is
highly conserved among cytokine receptors including the GHR. It may
thus also be a fundamentally important region for coupling GH occupancy
to GHR-JAK2 functional association.
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Concluding Remarks |
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TopAbstractIntroductionGeneral Aspects of GH...GHR and EpoR...Concluding RemarksReferences |
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Acknowledgments |
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Footnotes |
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Abbreviations: EBP, EpoR extracellular domain; Epo, erythropoietin; EpoR, Epo receptor; GHBP, GH binding protein; GHR, GH receptor.
Received August 22, 2001.
Accepted for publication October 2, 2001.
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TopAbstractIntroductionGeneral Aspects of GH...GHR and EpoR...Concluding RemarksReferences |
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