Endocrinology Vol. 142, No. 1 108-113
Copyright © 2001 by The Endocrine Society
Insulin-Like Growth Factor (IGF) Binding Protein-3 Inhibits Type 1 IGF Receptor Activation Independently of Its IGF Binding Affinity1
Jean-Marc Ricort2 and
Michel Binoux
Institut National de la Santé et de la Recherche
Médicale, Unité 515, Croissance, Différenciation et
Processus tumoraux, Hôpital Saint-Antoine, Paris, France
Address all correspondence and requests for reprints to: J-M Ricort, INSERM U.515, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris CEDEX 12, France. E-mail.
ricort{at}st-antoine.inserm.fr
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Abstract
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Insulin-like growth factor binding proteins (IGFBPs) regulate the
cellular actions of the IGFs owing to their strong affinities, which
are equal to or stronger than the affinity of the type 1 IGF receptor
(IGF-IR), the mediator of IGF signal transduction. We recently found
that IGFBP-3 modulates IGF-I binding to its receptor via a different
mechanism possibly involving conformational alteration of the receptor.
We have now investigated the effects of IGFBP-3 on the initial steps in
the IGF signaling pathway. MCF-7 breast carcinoma cells were
preincubated with increasing concentrations of IGFBP-3 and then
stimulated with IGF-I, des(1–3)IGF-I, or
[Q3A4Y15L16]-IGF-I,
the latter two being IGF-I analogs with intact affinity for the type 1
IGF receptor, but weak or virtually no affinity for IGFBPs. Stimulation
of autophosphorylation of the receptor and its tyrosine kinase activity
was dose-dependently depressed. At 2.5 nM, IGFBP-3 provoked
more than 50% inhibition of the stimulation induced by 3
nM des(1–3)IGF-1 and, at 10 nM, more than 80%
inhibition. Similar results were obtained with
[Q3A4Y15L16]-IGF-I.
Cross-linking experiments using iodinated or unlabeled IGFBP-3 and
anti-IGF-IR antibodies indicated that the inhibitory effects do not
involve direct interaction between IGFBP-3 and IGF-IR. The inhibition
appeared to be specific to IGFBP-3, because IGFBP-1 and IGFBP-5 at 10
nM had no significant effect. Also, inhibition was
restricted to the IGF receptor, because IGFBP-3 failed to inhibit the
tyrosine kinase activity of the insulin receptor stimulated by
physiological concentrations of insulin. Our results provide the first
demonstration that IGFBP-3 can specifically modulate the IGF-I
signaling pathway independently of its IGF-I-binding ability. They also
reveal a regulatory mechanism specific to the type 1 IGF receptor, with
no effect on insulin receptor activation.
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Introduction
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THE BIOLOGICAL EFFECTS of insulin-like
growth factors (IGFs) are mediated essentially through the type 1 IGF
receptor (IGF-IR), a transmembrane tyrosine kinase. Once activated,
this kinase phosphorylates such proteins as the insulin receptor
substrate (IRS), leading to activation of the different signaling
pathways involved in cell growth and metabolism (review in Ref.
1). IGFs bind with strong affinity to IGF binding proteins
(IGFBPs) that regulate their bioavailability and modulate their actions
(2). IGFBP-3 is the most abundant IGFBP, being present in
almost all tissues. Independently of its association with IGFs, it is
also capable of influencing cell growth (3, 4) and of
directly inducing apoptosis (5).
The mechanisms by which IGFBP-3 directly modulates IGF-I action remain
obscure. In our laboratory, competitive binding experiments using
des(1, 2, 3)IGF-I, an analog with weak affinity for IGFBPs, showed that
IGFBP-3 can either prevent ligand binding to IGF-IR or provoke its
dissociation, suggesting functional alteration of the receptor
(6). The repercussions of this alteration on the IGF
signaling pathway remained to be determined. This was the aim of the
present study, in which we have analyzed the effects of IGFBP-3 on
autophosphorylation and the tyrosine kinase activity of IGF-IR.
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Materials and Methods
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Antibodies and materials
Antiphosphotyrosine antibodies used for immunoblotting were
purchased from Upstate Biotechnology, Inc. (Lake Placid,
NY), antibodies to IGF-IR, from Calbiochem (La Jolla, CA),
and antimouse IgG antibodies coupled to horseradish peroxidase, from
Jackson ImmunoResearch Laboratories, Inc. (West Grove,
PA). Nonglycosylated recombinant human (rh)-IGFBP-3 (Coli)
was a generous gift from Celtrix Pharmaceuticals, Inc.
(Santa Clara, CA), h-IGFBP-1 purified from amniotic fluid and
rh-IGFBP-5 and rh-des(1, 2, 3)IGF-I were from GroPep Pty. Ltd. (Adelaide, Australia), rh-IGF-I was a gift from
Ciba-Geigy Ltd. (Basel, Switzerland) and rh-insulin was
from Eli Lilly & Co. (Saint Cloud, France).
rh-[Q3A4Y15L16]-IGF-I
was a generous gift from Dr. Cascieri, Merck Research Laboratories (Rahway, NJ). The labeled peptides used were
radio-iodinated by the chloramine-T method and purified by gel
filtration. All other biochemicals were from Sigma
(Saint-Quentin Fallavier, France).
Cell culture
The MCF-7 human breast cancer cell line was grown to 90–95%
confluency in DMEM supplemented with 10% FCS and 100 U/ml penicillin
and 100 µg/ml streptomycin. For 16–24 h before each experiment,
cells were starved in the same medium without serum. IGFBP-3 was
measured to checked that these cells do not produce IGFBP-3 under these
experimental conditions.
Immunodetection of phosphotyrosine-containing proteins
Cells were incubated with or without increasing concentrations
of IGFBP-3, IGFBP-1 or IGFBP-5 for 4 min at 37 C and then stimulated or
not with 3 nM IGF-I, des(1, 2, 3)IGF-I,
[Q3A4Y15L16]-IGF-I
or insulin for 3 min at 37 C. After solubilization of the cells,
proteins were separated by SDS-PAGE under reducing conditions and
transferred to polyvinylidene difluoride (PVDF) sheets as previously
described (7). The PVDF sheets were incubated with
antiphosphotyrosine antibodies, then with antimouse IgG antibody
coupled to horseradish peroxydase and proteins were revealed by
chemiluminescence (ECL, Amersham Pharmacia Biotech, Orsay,
France). The bands corresponding to IRS1 and IGF-IR were
quantified by densitometry scanning.
Binding experiments
Cells plated in 6-well or 100-mm dishes (Falcon) were incubated
for 5 h at 4 C with 125I-IGF-I
(106 cpm/dish, specific activity: approximately
45 ng/106 cpm) or
125I-des(1, 2, 3)IGF-I (2.5 x
105 cpm/well, approximately 76
ng/106 cpm), or
125I-[Q3A4Y15L16]-IGF-I
(2 x 105 cpm/well, approximately 56
ng/106 cpm), or
125I-IGFBP-3 (2.5 x
106 cpm/dish, approximately 22
ng/106 cpm). Nonspecific binding was determined
by addition of a 100-fold molar excess of unlabeled peptide.
Disuccinimidyl suberate (DSS) was then added to the medium to a final
concentration of 0.2 mM. After 30 min of incubation at 4 C,
the reaction was quenched for 5 min at 4 C with 50 mM
Tris-HCl, pH 7.4. Cells were washed twice and solubilized with the
buffer described above. In some experiments, proteins were separated by
SDS-PAGE under reducing conditions and revealed by autoradiography, or
transferred to PVDF sheets and immunodetected with anti-IGFBBP-3
antibodies as described above. In other experiments, solubilized
proteins were immunoprecipitated overnight at 4 C with antibodies to
IGF-IR coupled to protein G Sepharose. Immune pellets were washed 3
times with PBS, pH 7.4, 1% Nonidet P40. Immunoprecipitated proteins
were solubilized in Laemmli buffer, heated at 100 C for 2 min and
separated by SDS-PAGE under reducing conditions. The gel was then dried
and autoradiographed.
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Results
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IGFBP-3 inhibits IGF-I- and des(1, 2, 3)IGF-I- or
[Q3A4Y15L16]-IGF-I-stimulated
IGF-IR autophosphorylation and tyrosine kinase activity
Cell cultures at 37 C were used to study the effects of
preincubation with IGFBP-3 on ligand-stimulated autophosphorylation of
IGF-IR and its tyrosine kinase activity, as reflected by tyrosine
phosphorylation of its substrate, IRS1. MCF-7 breast cells were
incubated with or without increasing concentrations of IGFBP-3, then
stimulated with 3 nM IGF-I. After solubilization of the
cells, proteins were separated by SDS-PAGE and immunodetected using
antiphosphotyrosine antibodies.
Under basal conditions, there was no phosphorylation of tyrosine
residues in either IGF-IR or IRS1. Without IGFBP-3, IGF-I stimulated
autophosphorylation of IGF-IR and its tyrosine kinase activity (Fig. 1
). Preincubation of the cells with
IGFBP-3 dose-dependently inhibited IGF-I-induced IGF-IR
autophosphorylation and IRS1 phosphorylation. To demonstrate that such
inhibitory effect of IGFBP-3 could be independent of its ability to
bind IGF-I, the same experiments were performed using IGF-I analogs.
First, we tested des(1, 2, 3)IGF-I: IGFBP-3 dose-dependently inhibited
des(1, 2, 3)IGF-I-stimulated IGF-IR autophosphorylation and tyrosine
kinase activity (Fig. 2).
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Figure 1. Typical profile of the effects of rh-IGFBP-3 on
the IGF-I-induced autophosphorylation and tyrosine kinase activity of
the IGF-IR. MCF-7 cells were incubated with increasing concentrations
of rh-IGFBP-3 for 4 min at 37 C and then stimulated with 3
nM IGF-I for 3 min at 37 C before being homogenized.
Proteins were separated by SDS-PAGE, transferred to PVDF sheets, and
immunoblotted with antiphosphotyrosine antibodies as described in
Materials and Methods. Results are those of a typical
experiment in which duplicate samples were analyzed.
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Figure 2. Typical profile of the effects of rh-IGFBP-3 on
the des(1 2 3 )IGF-I-induced autophosphorylation and tyrosine kinase
activity of IGF-IR. MCF-7 cells were incubated with increasing
concentrations of rh-IGFBP-3 for 4 min at 37 C, then stimulated with 3
nM des(1 2 3 )IGF-I for 3 min at 37 C and treated as
described in Fig. 1 . Results are those of a typical experiment in which
duplicate samples were analyzed.
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Quantification of the bands corresponding to phosphorylated IGF-IR and
IRS1 showed that IGFBP-3 inhibited both activities induced by either
IGF-I or des(1, 2, 3)IGF-I to the same extent, with more than 50% at 2.5
nM, and 80% at 10 nM IGFBP-3 (Fig. 3).
Subsequently, we used
[Q3A4Y15L16]-IGF-I,
which has virtually no affinity for IGFBP-3. Again,
analog-stimulated IGF-IR autophosphorylation and tyrosine kinase
activity were inhibited by IGFBP-3 (Fig. 4).
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Figure 4. Effects of rh-IGFBP-3 on the
[Q3A4Y15L16]-IGF-I-induced
autophosphorylation and tyrosine kinase activity of IGF-IR. MCF-7 cells
were incubated with rh-IGFBP-3 (10 or 20 nM) for 4 min at
37 C, then stimulated with 3 nM
[Q3A4Y15L16]-IGF-I
for 3 min at 37 C and treated as described in Fig. 1. A typical profile
is shown, representing results obtained in a typical experiment in
which duplicate samples were analyzed.
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Inhibition of des(1, 2, 3)IGF-I-stimulation of the IGF signaling
pathway is IGFBP-3-specific
To check that the inhibition observed was specific to IGFBP-3,
the same experiments were run using IGFBP-1 or IGFBP-5. MCF-7 cells
were preincubated with increasing concentrations of IGFBP-1 or -5
before stimulation with des(1, 2, 3)IGF-I, then the cells solubilized and
proteins separated and immunodetected as described above. As shown in
Table 1, whichever the concentration of
IGFBP-1 or -5 used, there was no significant inhibition of either
des(1, 2, 3)IGF-I-induced activity.
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Table 1. Lack of effect of IGFBP-1 or IGFBP-5 on the
des(1 2 3 )IGF-I-induced autophosphorylation and tyrosine kinase
activity of IGF-IR
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IGFBP-3 fails to inhibit insulin receptor activation
Because there is strong homology between IGF-IR and the insulin
receptor, experiments were performed to test the ability of IGFBP-3 to
inhibit the insulin-induced tyrosine kinase activity of the insulin
receptor. In the MCF-7 cell model, insulin-induced autophosphorylation
of the insulin receptor could not be visualized, probably because of
the very small amounts of insulin receptor expressed. Nevertheless, the
few insulin receptors present on the cell surface were sufficient to
stimulate insulin-induced IRS1 phosphorylation.
MCF-7 cells were preincubated with IGFBP-3 (1 to 10 nM),
then stimulated with 3 nM insulin. Proteins were separated
by SDS-PAGE and immunodetected using antiphosphotyrosine antibodies as
described above. The insulin-stimulated tyrosine kinase activity of the
insulin receptor was reflected by tyrosine phosphorylation of IRS1.
Even at 10 nM, IGFBP-3 had no effect (Fig. 5).
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Figure 5. Lack of effect of rh-IGFBP-3 on the
insulin-induced tyrosine kinase activity of the insulin receptor. MCF-7
cells were incubated with increasing concentrations of rh-IGFBP-3 for 4
min at 37 C, then stimulated with 3 nM insulin for 3 min at
37 C and treated as described in Fig. 1. A typical profile is shown.
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Inhibition of des(1, 2, 3)IGF-I and
[Q3A4Y15L16]-IGF-I
binding to IGF-IR is IGFBP-3-specific
To demonstrate that the inhibitory action of IGFBP-3 on the
des(1, 2, 3)IGF-I-stimulated signaling pathway resulted from decreased
des(1, 2, 3)IGF-I binding to IGF-IR as shown by earlier competitive
binding experiments in liquid phase (6), MCF-7 cells were
incubated with 125I-des(1, 2, 3)IGF-I with or
without either IGFBP-3 or IGFBP-1, treated with the cross-linking agent
DSS and solubilized. Proteins were immunoprecipitated using anti-IGF-IR
antibodies, then separated by SDS-PAGE. As shown in Fig. 6, the association of
125I-des(1, 2, 3)IGF-I with the 
-subunit of
IGF-IR was dose-dependently inhibited by IGFBP-3, but not by IGFBP-1.
Subsequently, we used
125I-[Q3A4Y15L16]-IGF-I,
and again, IGFBP-3 inhibited analog binding to the IGF-IR -subunit
(Fig. 6).
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Figure 6. Effects of rh-IGFBP-3 on des(1 2 3 )IGF-I and
[Q3A4Y15L16]-IGF-I
binding to IGF-IR. MCF-7 cells were incubated with
125I-des(1 2 3 )IGF-I or
125I-[Q3A4Y15L16]-IGF-I
for 5 h at 4 C with or without IGFBP-3, or IGFBP-1 as control.
Cells were then treated with 0.2 mM DSS and lysed. Proteins
were immunoprecipitated with anti-type 1 IGF receptor antibodies as
described in Materials and Methods, then separated by
SDS-PAGE and revealed using a Storm imager (Amersham Molecular Dynamics, Inc.). A typical autoradiogram is shown.
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IGFBP-3 binds to cell surface proteins, but not to IGF-IR
In a first series of experiments, MCF-7 cells were incubated with
or without 125I-IGFBP-3 and a 100-fold molar
excess of unlabeled IGFBP-3 and treated with DSS. After solubilization,
proteins were analyzed by SDS-PAGE. As shown in Fig. 7A, 125I-IGFBP-3
cross-linked with at least three cell surface proteins with apparent
molecular masses of 30, 40, and 140 kDa. Because unlabeled IGFBP-3
totally displaced labeled IGFBP-3, this binding was specific. IGFBP-3
binding to these proteins was also demonstrated by immunoblotting using
anti-IGFBP-3 antibodies (Fig. 7B).
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Figure 7. IGFBP-3 interacts with cell surface proteins but
not with IGF-IR. Upper panel, MCF-7 cells were incubated
with 125I-IGFBP-3 for 5 h at 4 C with or without a
100-fold molar excess of unlabeled IGFBP-3 and treated with DSS. After
solubilization followed by SDS-PAGE, proteins were revealed either by
autoradiography using a Storm imager (Amersham Molecular Dynamics, Inc.) (A) or by immunoblotting with anti-IGFBP-3
antibodies (B). The immunoreactive protein of 100 kDa was nonspecific
because detected with the same intensity in the conditions with or
without IGFBP-3. Lower panel, MCF-7 cells were incubated
with or without 125I-IGF-I or 125I-IGFBP-3 for
5 h at 4 C with or without a 100-fold molar excess of unlabeled
IGF-I or IGFBP-3, respectively, and treated with DSS. Cells lysates
were immunoprecipitated with anti-IGF-IR antibodies as in Fig. 6. A
typical autoradiogram is shown (C).
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In a second series of experiments, MCF-7 cells were incubated with or
without 125I-IGF-I or
125I-IGFBP-3 with or without the corresponding
unlabeled protein, then treated with DSS. Cell lysates were
immunoprecipitated with anti-IGF-IR antibodies and the proteins
separated by SDS-PAGE. Figure 7C shows that
125I-IGF-I bound to IGF-IR under control
conditions, whereas 125I-IGFBP-3 did not.
Moreover, cross-linking experiments were performed using unlabeled
IGFBP-3, followed first by immunoprecipitation against either IGF-IR or
IGFBP-3, then by Western immunoblotting against either IGFBP-3 or
IGF-IR, respectively. Nowhere was a detectable signal observed (data
not shown).
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Discussion
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The present study provides the first evidence that
IGFBP-3 is capable of inhibiting the IGF-I signaling pathway
independently of its capacity for binding IGFs. IGF-I stimulation of
the initial steps in the pathway triggered by IGF-IR was markedly
reduced when MCF-7 cells were preincubated with IGFBP-3. The inhibition
was similar when IGF-IR autophosphorylation and tyrosine kinase
activity were stimulated using des(1, 2, 3)IGF-I, even at a 1:3 molar
ratio between IGFBP-3 and des(1, 2, 3)IGF-I. According to data from at
least two laboratories (6, 8), the affinity for rh-IGFBP-3
of des(1, 2, 3)IGF-I is nearly 100 times weaker than that of IGF-I, and it
could be inferred that the effects of IGFBP-3 on IGF-IR phosphorylation
were divorced from any binding to des(1, 2, 3)IGF-I. Nevertheless, to
confirm that no residual affinity for rh-IGFBP-3 of des(1, 2, 3)IGF-I may
be involved, we tested another analog,
[Q3A4Y15L16]-IGF-I,
whose affinity for IGFBP-3 is 1,000-fold weaker than that of IGF-I
(8). Similar results were obtained. It could therefore be
concluded that IGFBP-3 inhibition of IGF-IR phosphorylation is
unrelated to IGF sequestration. The tyrosine kinase activity of IGF-IR
is detectable via phosphorylation of one of its cytosolic substrates,
IRS1. In MCF-7 cells, IRS1 is the predominant cellular substrate of
IGF-IR (9) and IGFBP-3-induced inhibition of IGF-IR
activation would therefore block all the downstream elements of the
IGF-I signaling pathway.
Although the six IGFBPs possess highly conserved sequence
homology, especially in their C- and N-terminal domains
(10), their inhibitory or potentiating effects on IGF
action differ, not only in tune with their distinct characteristics,
but also according to tissue type and cellular environment
(2). IGFBP-1 and IGFBP-5, which have affinities for IGF-I
close to that of IGFBP-3 (2), had no effect on IGF-IR
activity. IGFBP-5 being structurally the most similar to IGFBP-3
(2, 10), our findings strongly suggest that IGFBP-3 is the
only IGFBP capable of inhibiting the IGF-I signaling pathway in MCF-7
cells. The cross-linking experiments using
125I-des(1, 2, 3)IGF-I and the results obtained with
[Q3A4Y15L16]-IGF-I
demonstrated that IGFBP-3 may impair IGF-I binding to its receptor, via
a mechanism that is dissociated from IGFBP-IGF binding. Such
intracellular regulation of IGF action would be complementary to the
well-established extracellular mechanism of IGF sequestration. The
molecular basis of the intracellular mechanism remains to be
elucidated. One possibility would be direct interaction between IGFBP-3
and IGF-IR, but immunoprecipitation of IGF-IR following incubation of
the cells with radiolabeled IGFBP-3 and cross-linking experiments using
unlabeled IGFBP-3 revealed no IGFBP-3-IGF-IR binding. As previously
demonstrated by Oh et al. (11), our studies
show that in our MCF-7 cells, IGFBP-3 is capable of interacting with
specific cell surface proteins (the nature of which remains unknown).
Thus, IGFBP-3 may interact with one of the putative IGFBP-3 receptors
that in turn may directly or indirectly modulate IGF-IR affinity and
activity. A further possibility is that this IGFBP-3-specific action
involves residues in the central domain of the protein, which is the
least conserved region among the IGFBPs. Further studies using directed
mutagenesis and/or construction of chimeric proteins will be required
to determine which amino acids are involved.
The insulin receptor and IGF-IR are similar tyrosine kinases capable of
phosphorylating and activating the same proteins. Nevertheless, the
effects of insulin and the IGFs at cellular level are quite distinct.
IGFs are generally associated with mitogenesis and insulin with
metabolism. Although there are data indicating that certain domains
(12) or residues (13) may in part be
responsible for activation of the different signaling pathways, no
clear evidence has as yet emerged to account for the specificity of the
signals generated by these two closely related receptors. Our results
demonstrate that the inhibitory action of IGFBP-3 is confined to the
IGF-I signaling pathway because it had no effect on the insulin-induced
tyrosine kinase activity of the insulin receptor. Therefore, an element
of the IGF system (IGFBP-3) specifically regulates IGF-I, but not
insulin, signaling. IGFs and IGFBP-3 coexist on the cell surface, and
it seems possible that the delicate balance between (ligand) activation
and (IGFBP-3) inhibition of IGF-IR would contribute toward
selecting the signal to be generated. Our results also indicate that
IGF-IR residues not shared with the insulin receptor may confer
sensitivity to inhibition by IGFBP-3.
In conclusion, our findings provide evidence of a new mechanism
in the regulation of the IGF-I signaling pathway, involving IGFBP-3.
Nevertheless, further study is required to elucidate the nature of this
mechanism and, specifically, to identify the protein(s) mediating the
effects of IGFBP-3 on IGF-IR.
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Acknowledgments
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We thank L. Harel for fruitful discussions and critical reading
of the manuscript.
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Footnotes
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1 This work was supported by the Institut National de la Santé
et de la Recherche Médicale and the University of Paris VI. 
2 Fellow of the Association pour la Recherche sur le Cancer.
Received May 30, 2000.
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C. K. Buckway, E. M. Wilson, M. Ahlsen, P. Bang, Y. Oh, and R. G. Rosenfeld
Mutation of Three Critical Amino Acids of the N-Terminal Domain of IGF-Binding Protein-3 Essential for High Affinity IGF Binding
J. Clin. Endocrinol. Metab.,
October 1, 2001;
86(10):
4943 - 4950.
[Abstract]
[Full Text]
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Abstract
Introduction
