G13-dependent Activation of MAPK by Thyrotropin

Büch, Thomas; Biebermann, Heike; Kalwa, Hermann; Pinkenburg, Olaf; Hager, D; Barth, Holger; Aktories, Klaus; Breit, Andreas; Gudermann, Thomas

doi:10.1074/jbc.m800211200

Cited by 38 publications

(19 citation statements)

References 60 publications

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“…These results indicate that LGR5 regulates Rho through G 12/13 . Buch et al (2008) demonstrated that the thyrotropin receptor activates ERK via the G 12/13 -Rho pathway, and our data showed that the SRE reporter, which is dependent on both ERK signaling, via ternary complex factor (TCF), and SRF, was induced by LGR5 for 48 h, followed by lysis and western analysis. Blots are representative of three independent experiments.…”

Section: Resultsmentioning

confidence: 52%

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon

Park

Kim

et al. 2013

Molecules and Cells

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Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5/GPR49) is highly expressed in adult stem cells of various tissues, such as intestine, hair follicles, and stomach.LGR5 is also overexpressed in some colon and ovarian tumors. Recent reports show that R-spondin (RSPO) family ligands bind to and activate LGR5, enhancing canonical Wnt signaling via the interaction with LRP5/6 and Frizzled. The identity of heterotrimeric G-proteins coupled to LGR5, however, remains unclear. Here, we show that Rho GTPase is a downstream target of LGR5. Overexpression of LGR5 induced SRF-RE luciferase activity, a reporter of Rho signaling. RSPOs, ligands for LGR4, LGR5, and LGR6, however, did not induce SRF-RE reporter activity in the presence of LGR5. Consistently, LGR5-induced activity of the SRF-RE reporter was inhibited by Rho inhibitor C3 transferase and RhoA N19 mutant, and knockdown of Gα 12/13 genes blocked the reporter activity induced by LGR5. In addition, focal adhesion kinase, NF-κB and c-fos, targets of Rho GTPase, were shown to be regulated by LGR5. Here, we have demonstrated, for the first time, that LGR5 is coupled to the Rho pathway through G 12/13 signaling.

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Section: Resultsmentioning

confidence: 52%

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Kwon

Park

Kim

et al. 2013

Molecules and Cells

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“…The functionality of the TSH receptor signalling was also evident, with a 2.17-fold increase in expression of Dio2 mRNA after treatment with TSH. The TSH receptor has been shown to couple with up to ten different G proteins representing members of all four families of G proteins (Ga i , Ga s , G q/11 and G 12/13 ), thereby activating adenylate cyclase, phophoslipase C and ERK1/2 (Laurent et al 1987, Allgeier et al 1994, Kursawe & Paschke 2007, Buch et al 2008. However, the functional significance of this potential promiscuity of G protein coupling is not understood, and the outcome of TSH receptor activation is likely to be dependent on the cell type expressing the receptor and the repertoire of available G proteins.…”

Section: Discussionmentioning

confidence: 99%

“…administration of TSH elicits a robust increase in Dio2 expression in the ependymal wall (Helfer et al 2013, Yoshimura 2013, and consequently increases local thyroid hormone availability. The activation of adenylate cyclase is a signal transduction pathway commonly associated with TSH receptor activation, but TSH receptors are known to couple with a diverse range of G proteins to activate several different pathways that potentially have multiple downstream consequences for responses to TSH (Laurent et al 1987, Allgeier et al 1994, Kursawe & Paschke 2007, Buch et al 2008. Our objective was to determine the pathways by which TSH signals within the cells of the ependymal wall, because these may have further consequences for the function of tanycytes and their regulation of the surrounding hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

Dual signal transduction pathways activated by TSH receptors in rat primary tanycyte cultures

Bolborea¹,

Helfer²,

Ebling³

et al. 2015

Journal of Molecular Endocrinology

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Tanycytes play multiple roles in hypothalamic functions, including sensing peripheral nutrients and metabolic hormones, regulating neurosecretion and mediating seasonal cycles of reproduction and metabolic physiology. This last function reflects the expression of TSH receptors in tanycytes, which detect photoperiod-regulated changes in TSH secretion from the neighbouring pars tuberalis. The present overall aim was to determine the signal transduction pathway by which TSH signals in tanycytes. Expression of the TSH receptor in tanycytes of 10-day-old Sprague Dawley rats was observed by in situ hybridisation. Primary ependymal cell cultures prepared from 10-day-old rats were found by immunohistochemistry to express vimentin but not GFAP and by PCR to express mRNA for Dio2, Gpr50, Darpp-32 and Tsh receptors that are characteristic of tanycytes. Treatment of primary tanycyte/ependymal cultures with TSH (100 IU/l) increased cAMP as assessed by ELISA and induced a cAMP-independent increase in the phosphorylation of ERK1/2 as assessed by western blot analysis. Furthermore, TSH (100 IU/l) stimulated a 2.17-fold increase in Dio2 mRNA expression. We conclude that TSH signal transduction in cultured tanycytes signals via Ga s to increase cAMP and via an alternative G protein to increase phosphorylation of ERK1/2.

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“…The follicle-stimulating hormone receptor (FSHR) and the LHCGR together with the TSHR constitute the sub-family of glycoprotein hormone receptors (GPHRs) (10). The TSHR is essential for thyroid growth and function (11–13) and activates different G-protein subtypes (14–17) and signaling pathways (18–20), whereby Gs- and Gq-induced signaling are probably of highest importance (13, 21–24). TSH and its receptor are required for thyroid hormone synthesis and release in the thyroid gland (25).…”

Section: Introductionmentioning

confidence: 99%

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

et al. 2017

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The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to understand the molecular activation mechanisms of this receptor comprehensively. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts toward TSHR structure elucidation.

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G13-dependent Activation of MAPK by Thyrotropin

Cited by 38 publications

References 60 publications

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

Dual signal transduction pathways activated by TSH receptors in rat primary tanycyte cultures

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

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