Download Internalization of the chicken growth hormone receptor complex and

Comparative Biochemistry and Physiology Part B 132 (2002) 299–308
Review
Internalization of the chicken growth hormone receptor complex and
its effect on biological functions夞
¨ a,*, Lieve Vleuricka, Marc Ederyb, Eddy Decuyperec, Veerle M. Darrasa
Eduard R. Kuhn
a
Laboratory of Comparative Endocrinology, Zoological Institute, K.U. Leuven, B-3000 Leuven, Belgium
INSERM U344, Faculte´ de Medicine Necker, 156, rue de Vaugirard, F-75730 Paris Cedex 15, France
c
Laboratory of Physiology and Immunology of Domestic Animals, Faculty of Agriculture and Applied Biological Sciences,
K.U. Leuven, B-3001 Leuven, Belgium
b
Received 27 January 2001; received in revised form 17 April 2001; accepted 2 May 2001
Abstract
In the chicken, as in mammals, GH is a pleiotropic cytokine that plays a central role in growth differentiation and
metabolism by altering gene expression in target cells. In the growing and adult chicken it stimulates gene expression
of IGF-I and inhibits gene transcription of the type III deiodinating enzyme (D3) and by doing so also increases T3
concentrations. GH binding to its receptor leads to internalization of the GH–GHR complex to the Golgi apparatus. This
process is linked to the episodic release pattern of GH during growth. At the same time, a sharp decline of the expression
of cGHR occurs at hatching. An in vitro study using a COS-7 cell line transfected with the cDNA of the chicken GHR,
revealed that GHR immunofluorescence was found in the perinuclear region and on the plasma membrane. Following
GH-induced internalization, GH and GHR were colocalized in endocytic and later in large lysosomal vesicles. Neither
receptor nor ligand was transferred to the nucleus as confirmed by confocal laser microscopy. The JAKySTAT pathway
however, as reported for mammalian GH receptors, mediated GH-induced gene transcription in chickens. 䊚 2002
Elsevier Science Inc. All rights reserved.
Keywords: Colocalization; Endocytosis of GH–GHR; Gene transcription; Golgi apparatus; Growth hormone; Ontogeny of receptors;
Thyroid; Growth
1. Introduction
Several hormones are involved in the control of
intermediary metabolism and growth of which the
夞 This paper was submitted as part of the proceedings of
the 20th Conference of European Comparative Endocrinologists, organized under the auspices of the European Society of
Comparative Endocrinology, held in Faro, Portugal, September
5–9, 2000.
*Corresponding author. Tel.: q32-16-32-3990; fax: q3216-32-4262.
E-mail address:
¨
[email protected] (E.R. Kuhn).
main ones can be divided into at least three groups:
a. GH and the insulin-like growth factors (IGF-I
and II): these hormones are hydrophylic and
have plasma membrane bound receptors.
b. The thyroid hormones and other growth factors.
c. Steroids.
During the life cycle of vertebrates, different
endocrine mechanisms may control growth and the
intermediary metabolism. So, during embryonic
and fetal growth body mass increases by both cell
multiplication and cell enlargement. GH seems not
1096-4959/02/$ - see front matter 䊚 2002 Elsevier Science Inc. All rights reserved.
PII: S 1 0 9 6 - 4 9 5 9 Ž 0 2 . 0 0 0 3 7 - 4
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¨ et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 299–308
E.R. Kuhn
Fig. 1. Relative importance of hormones in vertebrate growth: B, birth or hatching; and P, puberty.
to be implicated, but insulin, and possibly the IGFs
together with thyroid hormones may play a dominant role. Recently, GH receptor (GHR) binding
was demonstrated in the fetal rat liver together
with downstream signaling via the Janus kinase-2
tyrosine kinase and signal transducer and activator
of transcription (STAT1 and STAT5) (Phornphutkul et al., 2000), whereas in the chicken embryo
the GH gene is expressed in numerous extrapituitary sites (Harvey et al., 2000). This may implicate
the presence of other, still unknown activities for
GH during this period. Only after parturition or
hatching, GH will become important for growth
by stimulating the production of IGF and interacting profoundly with thyroid hormones. Gonadal
steroids will induce a growth spur by fusing the
epiphyseal cartilage left and by doing so, will
terminate at least the process of longitudinal
growth. All hormones again are involved in maintaining body weight in the postpuberal period and
in preparing the animal for a successful reproductive phase (Fig. 1).
Thyroid hormones and steroids are hydrophobic
and directly stimulate the rate of gene transcription
and protein synthesis by binding on nuclear receptors. However, GH will only be biologically active
after association with its receptor located in the
plasma membrane of a target cell. The existence
of dwarf lines in chicken mutated in their GHR
gene illustrates this principle (Decuypere et al.,
1991; Burnside et al., 1991). The consequent
physiological alterations are very similar to the
situation known in the human Laron type dwarf-
ism, which is also the result of a GHR dysfunction
(Brown et al., 1993). In both dwarf lines, embryonic and fetal growth is normal, stressing the fact
that GHR functionality is not required for normal
growth prenatally.
2. Link between GH productionybiological
activity and thyroid hormone
The activity of the somatotropic and thyrotropic
axes are tightly linked together in mammalian and
avian species.
In mammals, GH does not always control
growth rate and does not always stimulate somatomedin production, particularly during food
restriction and fetal life or hypothyroidism. In all
these situations this phenomenon is associated with
reduced T3 levels, suggesting a significant influence of thyroid function on GH action and body
growth. Thyroid hormones also stimulate the production of IGF and consequently fetal growth and
even body growth rate in dwarf animals is stimulated by T3 (Cabello and Wrutniak, 1989) (Figs.
1 and 2).
In the growing chicken, thyroid hormones do
play an important role in growth as indicated by
the administration of these hormones, by thyroidectomy or by treatment with anti-thyroid drugs
(King and May, 1984). There is also evidence for
the growth promoting effect of GH, of which
plasma levels are high in the young domestic fowl.
An injection of an antiserum to avian GH depresses
growth, which is restored by GH substitution.
¨ et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 299–308
E.R. Kuhn
301
Fig. 2. Growth hormone and gene expression related to growth.
Contrary to these observations, administrations of
chicken GH (cGH) failed to increase growth rate
in poultry (Vasilatos-Younken et al., 1988; Cogburn et al., 1997). This has been attributed to a
failure of GH supplementation to raise further the
already high plasma concentrations of T3, contrary
to the late embryonic situation. It has been shown
that after hatching low levels of the T3 inactivating
enzyme D3 are responsible for the high levels of
T3. Gene Expression of D3 is inhibited by GH,
mainly at the level of D3 gene transcription. This
effect of growth hormone on D3 expression per¨ et al., 1993; Darras et
sists throughout life (Kuhn
al., 1993, 1994). GH therefore controls both induction of IGF-I transcription (Rosselot et al., 1995)
and inhibition of D3 transcription in the chicken.
We would like to consider the down-regulation of
D3 by GH as part of its biological function in the
chicken (Fig. 2)
There is evidence that thyroid hormones may be
critical regulators for IGF-I in mammals and chicken (Cabello and Wrutniak, 1989). Also the thyroid
status profoundly influences circulating IGF-I bioactivity and local IGF-I production in a tissuespecific manner in the rat (Thomas et al., 1993),
and in the chicken, circulating IGF-I concentra-
tions were reported to decrease in chickens administered supplemental T3 (Vasilatos-Younken et al.,
1997; Tixier-Boichard et al., 1990), whereas hypothyroid chickens have a lower growth rate and a
lower IGF-I production (Decuypere et al., 1987).
3. Ontogeny of growth promoting hormones
and the GH-receptor
As in mammals during fetal intra-uterine life,
the chicken IGF-I secretory pattern seems not to
depend on GH secretion during embryogenesis.
Plasma concentrations of GH are first detectable
on day 17 of incubation, then rise gradually with
larger increases occurring during the week following hatching (Harvey et al., 1979). However, no
effect of GH releasing hormones on IGF-I concentration was observed during incubation (Huybrechts et al., 1985), whereas plasma T3
¨
concentrations are increased (Kuhn
et al., 1990).
The hepatic cGH receptor (cGHR) gene expression
is detectable at early ages in the embryonic chicken. Expression of the cGHR is transient, with a
sharp decline at hatching (Burnside and Cogburn,
1992). The variations of mRNA in chicken embryos are consistent with reported data on GH binding
Table 1
Correlation analysis of plasma GH concentrations and GH binding to liver microsomal fractions of saline- and GH-injected embryos
(18-day-old) over a period of 4 h following injection
Total receptors
Free receptors
Spearman correlation coefficient
Probability ))R)
Spearman correlation coefficient
Probability ))R)
Salineinjected
GHinjected
0.16
Ps0.50
0.24
Ps0.31
y0.85
P-0.0001
y0.81
P-0.0001
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¨ et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 299–308
E.R. Kuhn
Fig. 3. Ontogeny of GH, IGF-I, T3, GH binding and GHR expression (mRNA) in the chicken; H, hatching.
(Vanderpooten et al., 1991a,b). The sharp rise of
plasma GH, starting immediately before hatching,
seems to down-regulate GHR expression in late
embryonic and early post-hatch life (see Fig. 3).
The post-hatch cGHR expression gradually
increases. From week 2 post-hatch onwards, hormone secretion and receptor expression are mature
and GH-dependent growth can occur. Later, GH
secretion declines, whereas hepatic binding to the
cGHR and cGHR mRNA levels progressively
increase with age (Scanes and Harvey, 1981;
Vanderpooten et al., 1991a,b; Burnside and Cogburn, 1992; Mao et al., 1997).
Throughout development and growth, circulating GH concentrations are inversely related to
hepatic GHR expression, both at the protein and
mRNA level (Burnside and Cogburn, 1992).
Although the exact developmental factor regulating
GHR synthesis is not known, it is tempting to
speculate that GH down-regulates GHR expression, either directly or by IGF-I induction.
4. Receptor mediated endocytosis in the chicken
4.1. GH and GH-binding
In mammals, the processes following GH binding to the GHR have been studied in detail.
Subsequent to GH binding to the plasma
membrane-situated GHR, the GH–GHR complex
is internalized to an acid cell compartment where
degradation occurs (Barrazone et al., 1980; Murphy and Lazarus, 1984; Roupas and Herington,
1988). In chicken, several observations point to
the same mechanism.
a. Liver of growing chicks contains very little GH
receptors, though fast growth at this age is
paralleled by high plasma GH concentrations
(Vanderpooten et al., 1991a,b).
b. Adult laying hens which fasted for three days
exhibit higher circulating GH levels but lower
GH binding to liver membranes (Vanderpooten
et al., 1989).
c. Sex-linked dwarf chickens show low or no
hepatic GH binding but circulating GH is
increased (Scanes et al., 1983; Leung et al.,
¨
1987; Huybrechts et al., 1987; Kuhn
et al.,
1989; Vanderpooten et al., 1991b).
d. Following hypophysectomy plasma GH drops
below the detection limit but hepatic GHR are
increased. Moreover, the GHR increase by hypophysectomy is normalized by GH supplementation (Vanderpooten et al., 1991a).
e. And finally, the episodic release of GH secretion
in young chickens, resulting in pulsatile GH
concentrations, does not cause extensive GHR
down-regulation (Johnson, 1988, 1989). Moreover, administration of GH following this pattern, increases growth, whereas an injection or
infusion of GH does not (Vasilatos-Younken et
al., 1988; Cogburn et al., 1997).
Therefore, it was suggested that continuously
high circulating concentrations of GH down-regulate liver GHR number (Vanderpooten et al.,
¨ et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 299–308
E.R. Kuhn
1991a), and that the cell replaces internalized GH
receptors, either by de novo synthesis andyor by
recycling of GH receptors to the plasma membrane
(Fig. 3).
This conclusion is supported by a recent experiment, where 18-day-old embryos and 15-day-old
chicks were injected with 10 and 12.5 mg cGH,
respectively, and both GH plasma concentrations
and binding to liver microsomal fractions were
measured. A negative GH–GHR correlation coefficient is the main result, especially in embryos
where the GH-dependent decrease over a period
of 4 h in GH binding is striking (Vleurick, 1999)
(Table 1).
As this study was performed using microsomal
fractions that contain membrane vesicles derived
from miscellaneous cell compartments (Amar-Costesec et al., 1974), intracellular shifts of GHR
remained unnoticed. Therefore, a study was
planned to isolate subcellular fractions from livers
of saline- and GH-injected birds.
4.2. Intracellular distribution of GHRs
In mammals, the intracellular distribution of the
GHR was examined and it was found that, depending on their location in the cell, variations in
GHRs are differently related to changes in plasma
GH (Hochberg et al., 1993). Binding of human
GH to lactogenic receptors was demonstrated by
electron microscope autoradiography in Golgi
apparatus fractions prepared from rat liver (Bergeron et al., 1978).
Later, also somatogenic binding sites were
detected in Golgi fractions (Husman et al., 1985).
Immediately following a spontaneous plasma GH
pulse, somatogenic and lactogenic GH binding to
rat hepatic cell membrane fractions declines,
whereas in Golgi apparatus fractions binding
increases (Bick et al., 1989a,b).
Previous binding studies on chicken liver made
use of microsomal fractions or heterogeneous
membrane fractions prepared by differential centrifugation of a homogenate. Microsomes are
membrane vesicles of diverse subcellular origin.
Endoplasmic reticulum fragments are well represented, next to lysosomes, Golgi apparatus and
plasma membrane derived vesicles (Amar-Costesec et al., 1974). Since all these membranes may
contain GHRs, procedures to obtain highly purified
plasma membrane and Golgi apparatus fractions
from one liver are desirable in order to get a better
303
insight in internalization, degradation and recycling of GHRs in chicken liver.
Chicken liver plasma membranes minimally
contaminated with Golgi apparatus-derived vesicles, were prepared and identified using two marker enzymes, alkaline phosphatase (AP) and
alkaline phosphodiesterase (APD) (adapted from
Beaufay et al., 1974). Golgi apparatus fractions
were identified by galactosyltransferase (GT) as a
marker (Van Veldhoven and Mannaerts, 1991).
From the analysis of the fractions obtained by
differential centrifugation and from the discontinuous gradients, it is clear that in general GH
binding co-migrated with GT activity and not with
AP and APD activities.
Therefore, the majority of GH binding seems to
reside in the Golgi apparatus (Vleurick et al.,
1999a; Fig. 4). Also in rat, GHR number in plasma
membrane constitutes only a fraction of those in
the Golgi apparatus (Posner et al., 1979). As
removal of endogenous GH was difficult, our
results do not totally exclude the presence of
occupied receptors in the plasma membrane. However, it is known that GHR occupancy in adult
chicken liver is very low due to their low plasma
GH levels (Vanderpooten et al., 1989).
Although GHR concentration in the plasma
membrane is surely low, the absence of the GHR
from the plasma membrane is unlikely. It is generally accepted that GH receptors in the plasma
membrane are indispensable for transduction of
GH signals (Sotiropoulos et al., 1994). Moreover,
in earlier studies conducted in our laboratory it
was found that cGH is active in adult laying hens.
Within 2 h after injections of cGH plasma T4
levels are decreased and T3 levels increased
through a reduced hepatic breakdown of T3 (Darras et al., 1992). To provoke these GH-dependent
changes, only a minimal GHR number is required
if after binding the signal is multiplied in the
secondary messenger cascade. Signal transduction
by the cGHR involved the same molecules that
were identified for the mammalian GHR (Vleurick
et al., 1999c, see below)
The GH-binding study indicated that the high
GHR content of microsomal fractions prepared
from adult hen liver is largely due to its Golgi
localization. Since for GH sensitivity only receptors at the cell surface are relevant, the question
rises whether the intracellular GHR has a physiological role per se or is merely a consequence of
excess synthesis.
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E.R. Kuhn
It has been reported that transcription of the
GHR gene increases with age (Burnside and Cogburn, 1992) (Fig. 3). A large intracellular stock is
built up if constitutive GHR synthesis goes along
with low GHR degradation. When circulating GH
levels are low, as is the case in adult chickens,
binding and degradation of internalized receptors
are reduced. In general, the presence of intracellular receptors ensures quick reversal of transient
GH refractoriness as result of receptor internalization, since at least in mammals, GH receptors can
be transferred from the intracellular Golgi stock to
the plasma membrane (Hochberg et al., 1993).
4.3. Endocytosis of GH–GHR complex following
GH injections
Next to the receptor synthesis pathway, the
presence of intracellular receptors has also been
connected to endocytosis of hormone–receptor
complexes. When radioactive bovine GH is injected in rats, label appears subsequently in hepatic
plasma membrane, endocytic compartment and
lysosomes (Husman et al., 1988). The endosomal
fractions in the latter study were 40–50-fold
enriched in the Golgi marker GT. Other authors
also reported on the presence of GH binding in
the Golgi apparatus due to internalization.
Immediately following a spontaneous plasma
GH pulse, somatogenic and lactogenic GH binding
to rat hepatic cell membrane fractions declines,
whereas in Golgi fractions binding increases (Bick
et al., 1989b). Following binding to GH receptors
located in the plasma membrane, GH–GHR complexes enter the cell by endocytosis, ligand and
receptor dissociate and internalized receptors are
either degraded or recycled to the plasma
membrane, presumably through the Golgi apparatus (Hochberg et al., 1993). In the following
figure, the internalization model proposed by these
researchers is represented (Fig. 5).
In the adult chicken, 25 mgykg of cGH was
injected intravenously and total receptor binding
was measured 10 min and 1 h afterwards. A
positive correlation was found between plasma GH
and total GHR binding of the Golgi fraction in the
GH-injected but not in the saline group. No changes in free (unoccupied) receptors were observed.
These experiments therefore demonstrate that in
the chicken, as in its mammalian counterpart, the
GHR is internalized following GH binding (Vleurick et al., 1998).
4.4. In vitro study of GH–GHR interaction
Association of GH to its receptor leads to the
subsequent association of a second GHR molecule
(dimerization) (Cunningham et al., 1991). The
conserved regions in the intracellular domain intervene in receptor-mediated internalization (Allevato
et al., 1995; Vleurick et al., 1999c) and in signal
transduction by Janus kinase-2 (JAK-2) and signal
transducers and activators of transcription (STAT
proteins) (Finidori and Kelly, 1995; Vleurick et
al., 1999c).
However, in addition to the JAKySTAT secondary messenger pathway, a direct role in gene
transcription was also postulated for GH, GHR
and binding protein for GH (GHBP) in view of
their association with chromatin, subsequently to
nuclear translocation through the endosomal pathway (Lobie et al., 1991, 1992, 1994a,b).
In the chicken intracellular trafficking of GH
and its receptor was examined in COS-7 cells
transfected with the chicken GHR and detected
using immunofluorescence studies. In the absence
of GH, GHR immunofluorescence is found in the
perinuclear region and on the plasma membrane.
Internalization of both hormone and receptor is
induced by addition of GH after 20 min. Partial
colocalization of GH and GHR is found in endocytic and later, in large lysosomal vesicles. Neither
receptor nor ligand is transferred to the nucleus,
as confirmed by confocal laser microscopy (Vleu-
Fig. 4. Comparison of enrichment in marker enzyme and GH
receptors (GHR) in purified plasma membranes and Golgi
fractions. Values below one indicate enrichment of GHR content. AP, alkaline phosphatase; APD, alkaline phosphodiesterase; and GT, galactosyltransferase (Vleurick et al., 1999c).
¨ et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 299–308
E.R. Kuhn
Fig. 5. Schematic model of the spontaneous changes of the
hGH receptors and their internalization to Golgi membranes
(modified after Hochberg et al., 1993).
rick et al., 1998). Moreover, large amounts of
cGHBP were detected in the culture medium and
cell lysate of these cGHR-transfected cells, indicating that the internalization process may also
serve as the production site for GHBP, following
proteolytic cleavage of the GHR (Vleurick et al.,
1999b,c).
In summary, a model based on literature data
and the present results, resumes all the processes
involved in GH–cGHR interaction (Figs. 4–6).
GH-induced receptor dimerization promotes association and activation of JAK2 with the receptor.
The activated JAK2 is autophosphorylated and
phosphorylates the intracellular domain of the
GHR at multiple sites. The STAT proteins are then
recruited to the activated JAKyGHR complex and
305
become substrates for phosphorylation by JAK2.
Phosphorylated STAT proteins dimerize and dissociate from the receptor, and are translocated to
the nucleus where they bind consensus response
elements and affect expression of target genes. In
addition, adapter protein 2 (AP-2) is recruited
from the cytosol to the membrane by Tyr-based
internalization signals in the receptor’s intracellular
domain presumably with the help of a membranebound high affinity AP-2 docking protein (not
shown). Membrane-bound AP-2 complexes then
initiate clathrin coat assembly, a highly coordinated
process resulting in the entrapment and concentration of GH–GHR complexes. Membrane invagination presumably arises from rearrangements
within the clathrin lattice.
Finally, dynamin is required to pinch off the
clathrin-coated vesicle. An uncharacterized factor
(X) interacts with the identified b-turn, enhancing
internalization of GH by mammalian GHR as
compared to the cGHR. Clathrin is recycled from
the coated vesicles. In endocytic vesicles, the
slightly acid pH is sufficient to dissociate hormone
and receptor, enabling separate processing of GH
and GHR. Endocytic vesicles are either directed
to a degrading or a recycling pathway. However,
the extensive colocalization of GH and GHR
suggests that hormone and receptor are processed
in the same cell compartments. Endocytic vesicles
may fuse with lysosomes leading to the degrada-
Fig. 6. Schematic representation of the GH–GHR interaction and all subsequent events (Vleurick, 1999).
306
¨ et al. / Comparative Biochemistry and Physiology Part B 132 (2002) 299–308
E.R. Kuhn
tion of their content. GHBP, the extracellular
domain of the GHR, may be generated in the
lysosome by proteolysis of the full-length GHR.
Recycling vesicles return directly to the plasma
membrane or are transferred transiently to the
perinuclear region, where the Golgi apparatus is
located. In addition, to the recycled receptors, the
Golgi apparatus contains large amounts of newly
synthesized GH receptors, due to its role in protein
processing (Vleurick, 1999; Vleurick et al.,
1999b,c).
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