Disrupted TSH Receptor Expression in Female Mouse Lung Fibroblasts Alters Subcellular IGF-1 Receptor Distribution

Overview

Journal Endocrinology

Publisher Oxford University Press

Specialty Endocrinology

Date 2015 Sep 22

PMID 26389690

Citations 5

Authors

Stephen J Atkins

Stephen I Lentz

Roshini Fernando

Terry J Smith

Affiliations

Soon will be listed here.

Abstract

A relationship between the actions of TSH and IGF-1 was first recognized several decades ago. The close physical and functional associations between their respective receptors (TSHR and IGF-1R) has been described more recently in thyroid epithelium and human orbital fibroblasts as has the noncanonical behavior of IGF-1R. Here we report studies conducted in lung fibroblasts from female wild-type C57/B6 (TSHR(+/+)) mice and their littermates in which TSHR has been knocked out (TSHR(-/-)). Flow cytometric analysis revealed that cell surface IGF-1R levels are substantially lower in TSHR(-/-) fibroblasts compared with TSHR(+/+) fibroblasts. Confocal immunofluorescence microscopy revealed similar divergence with regard to both cytoplasmic and nuclear IGF-1R. Western blot analysis demonstrated both intact IGF-1R and receptor fragments in both cellular compartments. In contrast, IGF-1R mRNA levels were similar in fibroblasts from mice without and with intact TSHR expression. IGF-1 treatment of TSHR(+/+) fibroblasts resulted in reduced nuclear and cytoplasmic staining for IGF-1Rα, whereas it enhanced the nuclear signal in TSHR(-/-) cells. In contrast, IGF-1 enhanced cytoplasmic IGF-1Rβ in TSHR(-/-) fibroblasts while increasing the nuclear signal in TSHR(+/+) cells. These findings indicate the intimate relationship between TSHR and IGF-1R found earlier in human orbital fibroblasts also exists in mouse lung fibroblasts. Furthermore, the presence of TSHR in these fibroblasts influenced not only the levels of IGF-1R protein but also its subcellular distribution and response to IGF-1. They suggest that the mouse might serve as a suitable model for delineating the molecular mechanisms overarching these two receptors.

Citing Articles

Teprotumumab Divergently Alters Fibrocyte Gene Expression: Implications for Thyroid-associated Ophthalmopathy.

Fernando R, Smith T J Clin Endocrinol Metab. 2022; 107(10):e4037-e4047.

PMID: 35809263 PMC: 9516078. DOI: 10.1210/clinem/dgac415.

Teprotumumab as a Novel Therapy for Thyroid-Associated Ophthalmopathy.

Smith T Front Endocrinol (Lausanne). 2021; 11:610337.

PMID: 33391187 PMC: 7774640. DOI: 10.3389/fendo.2020.610337.

Building the Case for Insulin-Like Growth Factor Receptor-I Involvement in Thyroid-Associated Ophthalmopathy.

Smith T, Janssen J Front Endocrinol (Lausanne). 2017; 7:167.

PMID: 28096798 PMC: 5206614. DOI: 10.3389/fendo.2016.00167.

TSH Receptor Signaling Abrogation by a Novel Small Molecule.

Latif R, Realubit R, Karan C, Mezei M, Davies T Front Endocrinol (Lausanne). 2016; 7:130.

PMID: 27729899 PMC: 5037132. DOI: 10.3389/fendo.2016.00130.

Thyrotropin and Insulin-Like Growth Factor 1 Receptor Crosstalk Upregulates Sodium-Iodide Symporter Expression in Primary Cultures of Human Thyrocytes.

Morgan S, Neumann S, Marcus-Samuels B, Gershengorn M Thyroid. 2016; 26(12):1794-1803.

PMID: 27638195 PMC: 5175432. DOI: 10.1089/thy.2016.0323.

References

Clement S, Refetoff S, Robaye B, Dumont J, Schurmans S . Low TSH requirement and goiter in transgenic mice overexpressing IGF-I and IGF-Ir receptor in the thyroid gland. Endocrinology. 2001; 142(12):5131-9. DOI: 10.1210/endo.142.12.8534. View

Shimura H, Haraguchi K, Endo T, Onaya T . Regulation of thyrotropin receptor gene expression in 3T3-L1 adipose cells is distinct from its regulation in FRTL-5 thyroid cells. Endocrinology. 1997; 138(4):1483-90. DOI: 10.1210/endo.138.4.5048. View

De Meyts P, Whittaker J . Structural biology of insulin and IGF1 receptors: implications for drug design. Nat Rev Drug Discov. 2002; 1(10):769-83. DOI: 10.1038/nrd917. View

Marians R, Ng L, Blair H, Unger P, Graves P, Davies T . Defining thyrotropin-dependent and -independent steps of thyroid hormone synthesis by using thyrotropin receptor-null mice. Proc Natl Acad Sci U S A. 2002; 99(24):15776-81. PMC: 137792. DOI: 10.1073/pnas.242322099. View

Agretti P, Chiovato L, De Marco G, Marcocci C, Mazzi B, Sellari-Franceschini S . Real-time PCR provides evidence for thyrotropin receptor mRNA expression in orbital as well as in extraorbital tissues. Eur J Endocrinol. 2002; 147(6):733-9. DOI: 10.1530/eje.0.1470733. View

Pritchard J, Han R, Horst N, Cruikshank W, Smith T . Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves' disease is mediated through the insulin-like growth factor I receptor pathway. J Immunol. 2003; 170(12):6348-54. DOI: 10.4049/jimmunol.170.12.6348. View

Tramontano D, Cushing G, Moses A, Ingbar S . Insulin-like growth factor-I stimulates the growth of rat thyroid cells in culture and synergizes the stimulation of DNA synthesis induced by TSH and Graves'-IgG. Endocrinology. 1986; 119(2):940-2. DOI: 10.1210/endo-119-2-940. View

Parmentier M, Libert F, Maenhaut C, Lefort A, Gerard C, Perret J . Molecular cloning of the thyrotropin receptor. Science. 1989; 246(4937):1620-2. DOI: 10.1126/science.2556796. View

Feliciello A, Porcellini A, Ciullo I, Bonavolonta G, Avvedimento E, Fenzi G . Expression of thyrotropin-receptor mRNA in healthy and Graves' disease retro-orbital tissue. Lancet. 1993; 342(8867):337-8. DOI: 10.1016/0140-6736(93)91475-2. View

10.

Paschke R, Vassart G, Ludgate M . Current evidence for and against the TSH receptor being the common antigen in Graves' disease and thyroid associated ophthalmopathy. Clin Endocrinol (Oxf). 1995; 42(6):565-9. DOI: 10.1111/j.1365-2265.1995.tb02681.x. View

11.

Laugwitz K, Allgeier A, Offermanns S, Spicher K, Van Sande J, Dumont J . The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families. Proc Natl Acad Sci U S A. 1996; 93(1):116-20. PMC: 40189. DOI: 10.1073/pnas.93.1.116. View

12.

Shimura H, Miyazaki A, Haraguchi K, Endo T, Onaya T . Analysis of differentiation-induced expression mechanisms of thyrotropin receptor gene in adipocytes. Mol Endocrinol. 1998; 12(10):1473-86. DOI: 10.1210/mend.12.10.0175. View

13.

Tsui S, Naik V, Hoa N, Hwang C, Afifiyan N, Hikim A . Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves' disease. J Immunol. 2008; 181(6):4397-405. PMC: 2775538. DOI: 10.4049/jimmunol.181.6.4397. View

14.

Kleinau G, Krause G . Thyrotropin and homologous glycoprotein hormone receptors: structural and functional aspects of extracellular signaling mechanisms. Endocr Rev. 2009; 30(2):133-51. DOI: 10.1210/er.2008-0044. View

15.

Cianfarani F, Baldini E, Cavalli A, Marchioni E, Lembo L, Teson M . TSH receptor and thyroid-specific gene expression in human skin. J Invest Dermatol. 2009; 130(1):93-101. DOI: 10.1038/jid.2009.180. View

16.

Sehat B, Tofigh A, Lin Y, Trocme E, Liljedahl U, Lagergren J . SUMOylation mediates the nuclear translocation and signaling of the IGF-1 receptor. Sci Signal. 2010; 3(108):ra10. DOI: 10.1126/scisignal.2000628. View

17.

Smith T . Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases?. Pharmacol Rev. 2010; 62(2):199-236. PMC: 2879913. DOI: 10.1124/pr.109.002469. View

18.

Muller K, Fuhrer D, Mittag J, Kloting N, Bluher M, Weiss R . TSH compensates thyroid-specific IGF-I receptor knockout and causes papillary thyroid hyperplasia. Mol Endocrinol. 2011; 25(11):1867-79. PMC: 5417177. DOI: 10.1210/me.2011-0065. View

19.

Sarfstein R, Pasmanik-Chor M, Yeheskel A, Edry L, Shomron N, Warman N . Insulin-like growth factor-I receptor (IGF-IR) translocates to nucleus and autoregulates IGF-IR gene expression in breast cancer cells. J Biol Chem. 2011; 287(4):2766-76. PMC: 3268434. DOI: 10.1074/jbc.M111.281782. View

20.

Pollak M . The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012; 12(3):159-69. DOI: 10.1038/nrc3215. View