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Published in final edited form as: Pharmacol Ther. 2020 Feb 13;209:107502. doi: 10.1016/j.pharmthera.2020.107502

TSH/IGF1 Receptor Crosstalk: Mechanism and Clinical Implications

Christine C Krieger 1, Susanne Neumann 1, Marvin C Gershengorn 1
PMCID: PMC7187798  NIHMSID: NIHMS1564782  PMID: 32061922

Abstract

Increasing evidence of interdependence between G protein-coupled receptors and receptor tyrosine kinase signaling pathways has prompted reevaluation of crosstalk between these receptors in disease and therapy. Investigations into thyroid-stimulating hormone (TSH) and insulin-like growth factor 1 (IGF1) receptor crosstalk, and its application to the clinic have in particular shown recent progress. In this review, we summarize current insights into the mechanism of TSH/IGF1 receptor crosstalk. We discuss evidence that crosstalk is one of the underlying causes of TSHR-based disease and the feasibility of using combinations of TSH receptor and IGF1 receptor antagonists to increase the therapeutic index for the treatment of Graves’ hyperthyroidism and Graves’ ophthalmopathy.

Keywords: TSH receptor stimulating antibodies, Graves’ ophthalmopathy fibroblasts, receptor crosstalk, thyroid-stimulating hormone receptor, insulin-like growth factor 1 receptor

1. Introduction

Crosstalk between cell-surface G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) is a ubiquitous phenomenon that leads to broadening of the signaling responses initiated by the specific activation of one receptor (Hilger, Masureel, & Kobilka, 2018). In the case of GPCRs and RTK, crosstalk may occur after activation of either receptor; this has been termed bidirectional transactivation (Delcourt, Bockaert, & Marin, 2007; Pyne & Pyne, 2011). Although these interactions may occur at several steps in the signal transduction pathways, a large number of these involve GPCR-RTK interactions at the plasma membrane. Crosstalk of this type may be dependent on the generation of a ligand for the second receptor by activation of the first receptor or may be independent of ligand generation (Di Liberto, Mudo, & Belluardo, 2019). Crosstalk independent of ligand generation may result from “(r)eceptor-receptor interactions: when the binding of a ligand to the orthosteric or allosteric sites of one receptor causes, via direct allosteric interactions a change in the ligand recognition, decoding and trafficking processes of another receptor” (Kenakin, et al., 2010). However, an alternative to direct receptor-receptor interaction may be the formation of a multi-protein complex (“signalosome”) in which two receptors are brought in close proximity and may influence each other’s signaling. This type of receptor-receptor interaction appears to be the mechanism of crosstalk between the thyrotropin (thyroid-stimulating hormone, TSH) receptor (TSHR), which is a GPCR, and the insulin-like growth factor 1 receptor (IGF1R), which is an RTK.

In this review, we will describe findings that support the conclusion that TSH/IGF1 receptor crosstalk occurs and the molecular details involved in TSHR-IGF1R interaction. We will also summarize how TSH/IGF1 receptor crosstalk explains the pathophysiology of Graves’ hyperthyroidism, the most common cause of human hyperthyroidism, and Graves’ ophthalmopathy (GO, thyroid eye disease), and suggests treatment approaches for Graves’ disease.

2. TSH/IGF1 Receptor Crosstalk in Cells in Culture

Functional interactions between TSHR and IGF1R in thyrocytes in vitro (Eggo, Bachrach, & Burrow, 1990; Kimura, et al., 2001; Santisteban, Kohn, & Di Lauro, 1987; Tramontano, Cushing, Moses, & Ingbar, 1986) have been reported for many years; however, the majority of these studies were performed in rodent cell lines and whether they are accurate models of human cells is not clear. Functional interactions between TSHR and IGF1R have also been shown in orbital fibroblasts from patients with Graves’ disease in vitro (Chen, et al., 2014; Hoa, et al., 2012; Kumar, Iyer, Bauer, Coenen, & Bahn, 2012; Tsui, et al., 2008). Our own studies have been performed in primary cultures of Graves’ orbital fibroblasts/preadipocytes (GOFs), primary cultures of normal, differentiated, human thyrocytes obtained from the contralateral lobe of patients at surgery for thyroid cancer, and a human bone osteosarcoma epithelial cell line (Krieger, et al., 2019; Krieger, Neumann, Place, Marcus-Samuels, & Gershengorn, 2015; Krieger, et al., 2016; Morgan, Neumann, Marcus-Samuels, & Gershengorn, 2016).

In many studies in GOFs, activation of TSHR-and IGF1R-stimulated secretion of hyaluronan (hyaluronic acid, HA) was measured as a biologic response because increased HA secretion in the orbit is a major component of the pathophysiology of GO. To determine whether TSHR-IGF1R interaction was dependent on the generation of IGF1 after stimulating TSHR, we measured the effect of an IGF1R blocking antibody, AF305. Figure 1 illustrates that AF305, as expected, inhibits stimulation of HA secretion by IGF1 but had no effect on stimulation by TSH (Krieger, unpublished observation). Thus, stimulation of HA secretion initiated by TSHR activation is independent of autocrine/paracrine effects of IGF1 generation.

Figure 1. TSH/IGF1 Receptor crosstalk in GOFs is independent of IGF1R ligand generation.

Figure 1.

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One previously described mechanism for receptor transactivation between GPCRs and RTKs occurs when GPCR activation leads to the release of a RTK ligand (Delcourt, et al., 2007). In this scenario, preventing RTK ligand from binding to its receptor would inhibit crosstalk. This model was tested in GOFs using an IGF1R blocking antibody, AF305. Here, TSHR was activated by its cognate ligand, TSH, without (gray bars) or with AF305 (black bars). Even though AF305 fully blocked IGF1 binding to and thereby activation of IGF1R, TSH induced hyaluronan secretion was unchanged in the presence of AF305. Thus, TSHR activation did not cause IGF1R activation by releasing IGF1.

A primary indication of TSHR-IGF1R interaction was our observation that simultaneous activation by TSH and IGF1 synergistically increased HA secretion in GOFs; there were increases in both potency and efficacy of TSH (Krieger, et al., 2015) (Fig. 2). Further evidence in support of TSH/IGF1 receptor crosstalk were our findings that an IGF1R small molecule antagonist, linsitinib, inhibited HA stimulation by TSH and that some IGF1R blocking antibodies inhibited stimulation by TSH (Chen, et al., 2014). These findings were complemented by our results using a monoclonal TSHR-stimulating antibody M22, which was derived from a patient with Graves’ hyperthyroidism (Sanders, et al., 2003). We found that the dose-response to M22 was biphasic and that the IGF1R antagonist, linsitinib, inhibited the higher potency (lower M22 dose) phase but had no effect on the lower potency (higher M22 dose) phase (Fig. 3A). Figure 3B illustrates a model of TSH/IGF1 receptor crosstalk stimulated by M22. We (Krieger, et al., 2016; Place, Krieger, Neumann, & Gershengorn, 2017) and others (Chen, et al., 2014; Kumar, et al., 2012) provided additional evidence of crosstalk by observing that stimulation by M22 was inhibited by some, but not all, IGF1R blocking antibodies as described below.

Figure 2. Synergistic activation of TSHR with simultaneous TSH and IGF1 treatment.

Figure 2.

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Synergistic activation is often described as when the combination of two treatments is greater than the additive effects of each individual treatment. In GOFs, hyaluronan secretion was stimulated with increasing doses of TSH alone (black circles) or TSH with 100 ng/mL IGF1 (gray circles). The maximally effective dose of TSH + IGF1 was greater than TSH alone + IGF1 alone (white and black striped bar). Furthermore, in the presence of IGF1, TSH potency (dotted line) was approximately 100-fold higher than the potency of TSH in the absence of IGF1 (dashed line). This shift in potency was not seen in the reverse situation, the IGF1 dose-response with TSH, indicating that crosstalk originates at TSHR (Place, et al., 2017).

Figure 3. Model of M22-induced TSH/IGF1 receptor crosstalk in GOFs.

Figure 3.

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(A) In GOFs, hyaluronan secretion in response to stimulating TSHR antibody M22 is biphasic (dashed line). In the presence of the IGF1R kinase inhibitor linsitinib, the high-potency phase is lost and the M22 dose-response becomes monophasic (solid line). Therefore, the high-potency phase is IGF1R-dependent and the low-potency phase is IGF1R-independent. (B) In our model, M22 can activate multiple signaling pathways through TSHR. When M22 activates TSH/IGF receptor crosstalk (gray arrows), TSHR uses IGF1R associated down-stream effectors. Alternatively, TSHR can use its own molecular machinery (black arrows). Both pathways converge further downstream to induce hyaluronan secretion (black and gray striped arrow).

We found evidence for TSH/IGF1 receptor crosstalk in two other human cell systems in culture. In primary cultures of human thyrocytes, Morgan et al. (Morgan, et al., 2016) found that linsitinib inhibited TSH-induced upregulation of the expression of sodium-iodide symporter, which is a critical mediator of thyroid hormone biosynthesis. In U2OS cells, an osteosarcoma epithelial cell line, overexpressing TSHRs, Krieger et al. (Krieger, et al., 2019) showed that knockdown of IGF1R inhibited TSH induced secretion of osteopontin, which is a protein involved in bone homeostasis.

3. The Role of ERK and β-Arrestin 1 in TSH/IGF1 Receptor Crosstalk

Models of GPCR-RTK interaction have been proposed in which signalosomes comprised of GPCR, G protein and β-arrestin are in dynamical complexes, which may be influenced by ligand binding, are involved in GPCR/RTK crosstalk (Hilger, et al., 2018; Pyne & Pyne, 2011). In GOFs, Krieger et al. (Krieger, Perry, Morgan, Kahaly, & Gershengorn, 2017) demonstrated that the increased potency for TSH seen for HA secretion was also found on ERK½ phosphorylation when cells were stimulated simultaneously by TSH and IGF1.

β-arrestin 1 and β-arrestin 2 are key elements in the regulation of TSHR-mediated signaling (Kopp, 1997). While β-arrestin 2 plays a predominant role in TSHR-desensitization (Boutin, Eliseeva, Gershengorn, & Neumann, 2014; Frenzel, Voigt, & Paschke, 2006), β-arrestin 1 is primarily involved in activatory TSHR signaling. For example, TSHR stimulation of ERK½ phosphorylation was demonstrated to be mediated by β-arrestin 1 (Boutin, Eliseeva, Gershengorn, & Neumann, 2014). Likewise, activation of the IGF1R by IGF1 induces β-arrestin 1-mediated activation of the ERK pathway (Lin, Daaka, & Lefkowitz, 1998). β-arrestin knockdown was shown to inhibit TSH/IGF1 receptor crosstalk (Krieger, et al., 2019). Krieger et al. (2019) showed that β-arrestin 1 was also a member of the pre-formed complex including TSHR and IGF1R and its presence was necessary for complex stability in GOFs, human thyrocytes and U2OS cells. This study used a Proximity Ligation Assay (PLA) to measure co-localization of TSHR and IGF1R (Fig. 4). PLA between TSHR and IGF1R revealed that these receptors co-localized (were within 40 nm of each other) under basal conditions in all three cell types; that is, ligand binding was not necessary for this signaling complex to form (Fig 4A).

Figure 4. TSHR/IGF1R signaling complex depends on β-arrestin 1.

Figure 4.

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TSHR/IGF1R signaling complexes were detected using a Proximity Ligation Assay and visualized with fluorescent microscopy. Orange dots represent PLA signals, and a DNA/RNA stain (green) was used to determine cell number. (A) A representative confocal image of GOFs shows the number of signaling complexes under basal conditions. (B) In GOFs with reduced β-arrestin 1 protein expression, the number of dots is significantly reduced. (C) The bars depict the average Dots/cell from several images. *p < 0.05 (Krieger, et al., 2019). (D) PLA shows that TSHR and IGF1R are within 40 nm of each other, and that distance would allow for a protein complex. A model of a TSHR/IGF1R signaling complex is consistent with the idea that β-arrestin’s involvement is likely through an undefined protein complex rather than direct interactions with each receptor.

This observation confirmed an earlier report of TSHR/IGF1R co-immunoprecipitation (Tsui, et al., 2008) and indirectly supported the idea that crosstalk occurs proximal to the receptor, but did not demonstrate the necessity of receptor co-localization to crosstalk. Next, Krieger et al. (Krieger et al, 2019) used PLA to measure TSHR/IGF1R co-localization following knock-down of β-arrestins. In all studied cell types, knock-down of β-arrestin 1 reduced receptor co-localization (Fig 4B). In thyrocytes and U2OS cells, these effects were partial. In GOFs co-localization of TSHR and IGF1R was completely prevented, coinciding with complete inhibition of functional crosstalk (Fig 4C). These findings together indicate that TSHR and IGF1R are likely to be in a pre-formed signaling complex in order to crosstalk and demonstrate that β-arrestin 1 stabilizes this complex in the absence of ligand binding (Fig 4D). We suggest that a subpopulation of receptors likely form TSHR/IGF1R signaling complexes in any tissue where both receptors are endogenously expressed. What other binding partners are members of this signaling complex and how it is regulated are open questions.

4. Crosstalk in the pathogenesis and treatment of Graves’ disease

As described above, the M22 dose-response for stimulation of HA secretion is biphasic, suggesting that TSHR utilized at least two different signaling pathways to increase HA. Importantly, only one phase was inhibited by an IGF1R antagonist. We showed that M22 binds to TSHR but does not bind to IGF1R (Krieger, Neumann, Marcus-Samuels, & Gershengorn, 2017) and provided additional evidence that immunoglobulins from patients with GO (GO-Igs) do not directly activate IGF1R (Marcus-Samuels, et al., 2018). Because M22 was specific for TSHR, we concluded that the linsitinib-sensitive phase originated from TSHRs engaged in crosstalk with IGF1R. Therefore, in the M22-GOF system, one could separately demonstrate effects on IGF1R-dependent and -independent signaling pathways. We used this to characterize different properties of IGF1R blocking antibodies (Krieger, et al., 2016). Two different IGF1R antibodies, 1H7 and AF305, were compared in their ability to counter M22 stimulation in GOFs. Both these antibodies had the ability to block binding of IGF1 to IGF1R. Yet only 1H7 was able to inhibit the linsitinib-sensitive phase of the M22 biphasic dose-response. 1H7, but not AF305, could therefore serve as an inhibitor of crosstalk originating from TSHR stimulation.

To determine whether M22 was representative of the polyclonal antibodies that comprise the immunoglobulins in the blood of patients with GO (GO-Igs) and thereby determine whether TSH/IGF1 receptor crosstalk was involved in GO-Igs effects on GOFs, we compared the effects of 1H7 and AF305 to inhibit TSHR stimulation by GO-Igs (Krieger, et al., 2016). In an attempt to exclude an effect of other active components in the patient’s serum samples, Igs were purified from whole serum by thiophilic affinity chromatography, and subsequently the preparations were dialyzed. In the majority of samples, 1H7 partially inhibited GO-Igs stimulation while AF305 had little to no effect. We concluded that GO-Igs produced in these patients could activate crosstalk in TSHR/IGF1R signaling complexes, and activation of this pathway contributed to the pathogenesis of GO.

Knowing that GO-Igs activate TSH/IGF1 receptor crosstalk may help us in designing new treatments and in understanding the mechanism(s) of action of new therapies currently being tested. There are advantages to developing combination treatments to target GPCR-RTK signaling platforms as suggested by Pyne & Pyne (Pyne & Pyne, 2011) and recently supported by Place et al. (Place, et al., 2017) in GOFs. The question of this study was whether inhibiting TSH/IGF1 receptor crosstalk alone was sufficient for suppressing M22 induction of HA secretion. We found that an IGF1R antibody capable of inhibiting TSHR/IGF1R crosstalk cannot fully inhibit the induction of HA by TSHR-stimulating antibodies because stimulation proceeds via the IGF1R-independent pathway. In contrast, because TSH/IGF1 receptor crosstalk is initiated at TSHR, targeting that receptor with a small molecule antagonist (NCGC00242364) was fully efficacious.

An intriguing finding by Place et al. (Place, et al., 2017) was that treatment comprising low concentrations of TSHR and IGF1R antagonists was as efficacious as single treatment using a maximally effective concentration of a TSHR antagonist alone that is more effective than antagonism of IGF1R (Fig. 5). In other words, the putative clinically effective dose of each antagonist was reduced when used together (Fig. 6). This finding is significant in light of the fact that single therapy targeting IGF1R has advanced further in clinical trials (Kahaly, 2019; Patel, Yang, & Douglas, 2019) than single therapy targeting TSHR, currently in phase I clinical trials (Furmaniak, et al., 2018; Singh, 2016). IGF1R targeted single therapy with Teprotumumab™ has been effective in treating GO (Mohyi & Smith, 2018). The recent findings suggest that Teprotumumab™, like 1H7, acts to antagonize crosstalk in GOFs. However, since IGF1 signaling is integral to cellular processes in many cell types and IGF1R is expressed in many tissues and has a high degree of homology with the insulin receptor, IGF1R monotherapies have a high likelihood of off-target effects, recently reviewed by Simpson et al. (Simpson, Petnga, Macaulay, Weyer-Czernilofsky, & Bogenrieder, 2017), Osher et al. (Osher & Macaulay, 2019), and Manzella et al. (Manzella, et al., 2019). We suggest these effects may be avoided at lower concentrations of Teprotumumab™ if used in combination with a TSHR antagonist (Fig. 6). This would expand the possible repertoire of therapeutic agents.

Figure 5. Combination treatments efficiently inhibit TSH/IGF1 receptor crosstalk.

Figure 5.

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Like M22, antibodies purified from six different GO patient sera (GO-Igs) induce hyaluronan secretion through TSH/IGF1 receptor crosstalk in GOFs (dark gray bars). Inhibition of TSHR signaling or blocking TSHR/IGF1R crosstalk with a 50% inhibitory concentration (IC50) dose of a small molecule TSHR antagonist (TSHR antag) or the IGF1R antibody, 1H7, respectively, inhibits hyaluronan secretion, but inhibition is not complete (light gray bars). Yet, these same doses, when combined, are fully efficacious (black bar) (Place, et al., 2017).

Figure 6. Model of inhibition of TSH/IGF1 receptor crosstalk to treat Graves’ disease.

Figure 6.

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This model is based primarily on studies with Graves’ orbital fibroblasts in cell culture. TSHR-stimulating antibodies, M22 or GO-Igs, activate either IGF1R-dependent (gray arrows) or IGF1R-independent (black arrows) signaling pathways, both of which converge to induce hyaluronan secretion (black/gray striped arrow). Destabilizing crosstalk with an IGF1R inhibitory antibody (IGF1R Ab) or kinase inhibitor alone may reduce hyaluronan secretion but cannot inhibit the IGF1R-independent pathway(s) activated by TSHR. Preventing activation of TSHR with either an antagonist or inhibitory antibody blocks both pathways.

A similar situation exists when considering recent efforts to develop drugs targeting β-arrestin. Because of β-arrestin’s now widely accepted role in GPCR biased signaling (recently reviewed in (Bagnato & Rosano, 2019; Gurevich & Gurevich, 2019; Seyedabadi, Ghahremani, & Albert, 2019; Smith, Lefkowitz, & Rajagopal, 2018), this protein has become an attractive target for a variety of disorders involving GPCRs (Bond, Lucero Garcia-Rojas, Hegde, & Walker, 2019; van Gastel, et al., 2018). However, β-arrestin is also ubiquitously expressed, therefore therapies targeted at β-arrestin have the potential to produce adverse side effects. In an analogous fashion, combination GPCR/β-arrestin therapies could increase specificity to tissues where only the two proteins of interest are expressed and lower possible adverse effects.

In the long-term, treatments targeting TSHR will likely be better approaches for treatments of Graves’ disease. However, much work needs to be done before these ideas can be translated to patient care. This model heavily relies on in vitro studies, which further rely on the availability of research tools such as IGF1R and TSHR inhibitory and stimulating antibodies. Efforts to expand the molecular toolkit are in progress (Pearce, et al., 2019). While advances have been made, technical hurdles remain, including the fact that TSHR has not yet been crystallized making the design of small molecule ligands a trial and error process. Nevertheless, because TSHR engages in crosstalk with IGF1R, combination treatments could be designed to improve the therapeutic index by targeting both receptors.

Abbreviations

GPCR

G protein-coupled receptor

RTK

receptor tyrosine kinases

TSH

thyrotropin, thyroid-stimulating hormone

TSHR

thyrotropin receptor

IGF1

insulin-like growth factor 1

IGF1R

insulin-like growth factor 1 receptor

GD

Graves’ disease

GO

Graves’ ophthalmopathy, thyroid eye disease

GOFs

Graves’ orbital fibroblasts/preadipocytes

HA

hyaluronan, hyaluronic acid

ERK

extracellular signal-regulated kinases

βARR

β-arrestin

PLA

Proximity Ligation Assay

GO-Igs

purified GO antibodies

Footnotes

Conflict of Interest Statement:

The authors declare that there are no conflicts of interest.

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