Deletions in the third intracellular loop of the thyrotropin receptor. A new mechanism for constitutive activation.

The Journal of Biological Chemistry
P WonerowRalf Paschke

Abstract

Gain-of-function mutations of the thyrotropin receptor (TSHR) gene have been invoked as one of the major causes of toxic thyroid adenomas. In a toxic thyroid nodule, we recently identified a 9-amino acid deletion (amino acid positions 613-621) within the third intracellular (i3) loop of the TSHR resulting in constitutive receptor activity. This finding exemplifies a new mechanism of TSHR activation and raises new questions concerning the function of the i3 loop. Because the i3 loop is thought to be critical for receptor/G protein interaction in many receptors, we systematically reexamined the role of the TSHR's i3 loop for G protein coupling. Thus, various deletion mutants were generated and functionally characterized. We identified an optimal deletion length responsible for constitutive activity. If the number of deleted amino acids was reduced, elevated basal cAMP accumulation was found to be concomitantly diminished. Expansion of the deletion dramatically impaired cell surface expression of the receptor. Shifting the deletion toward the N terminus of the i3 loop resulted in unaltered strong constitutive receptor activity. In contrast, translocation of the deletion toward the C terminus led to significantly reduced basal cAMP...Continue Reading

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Citations

Sep 7, 2006·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Maren ClausRalf Paschke
Jul 20, 1999·Molecular and Cellular Endocrinology·T SchönebergT Gudermann
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Sep 25, 2008·The Journal of Biological Chemistry·Melissa J S CheeWilliam F Colmers
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May 10, 2008·Thyroid : Official Journal of the American Thyroid Association·Hulya Iliksu GozuRalf Paschke
Jun 9, 2009·Thyroid : Official Journal of the American Thyroid Association·Isabel CastroJoaquin Lado-Abeal
Nov 21, 2007·Endocrine Journal·Eijun NishiharaAkira Miyauchi
Jun 9, 2001·Biochemical and Biophysical Research Communications·A ChenK A Jacobson
Nov 24, 2004·Pharmacology & Therapeutics·Torsten SchönebergKatrin Sangkuhl
Mar 24, 2016·Cancer Letters·Ying LiuTian-Rui Xu
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Mar 1, 2020·Thyroid : Official Journal of the American Thyroid Association·Alexandra StephensonRalf Paschke
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Feb 11, 1999·Molecular Endocrinology·A SchulzT Gudermann
Nov 22, 2020·Pharmacological Reviews·Torsten Schöneberg, Ines Liebscher

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