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Cited by 68Receptor Mechanisms and SignalingThyroid Disorders and TreatmentsProtein Kinase Regulation and GTPase Signaling

Gβγ Dimers Released in Response to Thyrotropin Activate Phosphoinositide 3-Kinase and Regulate Gene Expression in Thyroid Cells

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Zaballos, Miguel A., Garcia, Bibian, Santisteban, Pilar·2008·Molecular Endocrinology
DOI 10.1210/me.2007-0093PMC PMC5419518
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Abstract

Signaling by TSH through its receptor leads to the dissociation of trimeric G proteins into Galpha and Gbetagamma. Galphas activates adenylyl cyclase, which increases cAMP levels that induce several effects in the thyroid cell, including transcription of the sodium-iodide symporter (NIS) gene through a mechanism involving Pax8 binding to the NIS promoter. Much less is known about the function of Gbetagamma in thyroid differentiation, and therefore we studied their role in TSH signaling. Gbetagamma overexpression inhibits NIS promoter activation and reduces NIS protein accumulation in response to TSH and forskolin. Conversely, inhibition of Gbetagamma-dependent pathways increases NIS promoter activity elicited by TSH but does not modify forskolin-induced activation. Gbetagamma dimers are being released from the Gs subfamily of proteins, because cholera toxin mimics the effects elicited by TSH, whereas pertussis toxin has no effect on NIS promoter activity. We also found that TSH stimulates Akt phosphorylation in a phosphoinositide 3-kinase (PI3K)-dependent and cAMP-independent manner. This is mediated by Gbetagamma, because its overexpression or specific sequestration, respectively, increased or reduced phosphorylated Akt levels upon TSH stimulation. Gbetagamma sequestration increases NIS protein levels induced by TSH and Pax8 binding to the NIS promoter, which is also increased by PI3K inhibition. This is, at least in part, caused by Gbetagamma-mediated Pax8 exclusion from the nucleus that is attenuated when PI3K activity is blocked. These data unequivocally demonstrate that Gbetagamma released by TSH action stimulate PI3K, inhibiting NIS gene expression in a cAMP-independent manner due to a decrease in Pax8 binding to the NIS promoter.

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Authors
Zaballos, M. A., Garcia, B., & Santisteban, P.
Affiliations
  • Consejo Superior de Investigaciones Científicas (ES)
  • Instituto de Investigaciones Biomedicas “Alberto Sols,” Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28029 Madrid, Spain
ORCID
Venue
Molecular Endocrinology
Publisher
The Endocrine Society
Published
2008-05-01
Volume
22
Issue
5
Pages
1183-1199
ISSN
  • 0888-8809 (ISSN-L)
  • 1944-9917
DOI
10.1210/me.2007-0093
PMC
PMC5419518
OpenAlex
W2094147091
Cited by
68
References
2
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 4 · 2015: 10 · 2014: 3 · 2013: 1 · 2012: 5
FWCI
2.03
Type
journal article
Language
en
Open access
Locations
  • Molecular Endocrinology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
Funders
  • Comunidad de Madrid
  • Ministerio de Economía y Competitividad (RD06/0020)
  • Instituto de Salud Carlos III (RD06/0020)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
Gβγ dimer, TSH receptor, phosphatidylinositol 3-kinase, Akt phosphorylation, sodium iodide symporter, PAX8, thyroid differentiation, cAMP-independent signaling, cholera toxin, pertussis toxin, nuclear translocation
MeSH terms
PAX8 Transcription Factor, Cyclic AMP, Animals, Cell Line, Enzyme Activation, Flow Cytometry, Colforsin, Models, Biological, Phosphorylation, Rats, Inbred F344, Thyroid Gland, Thyrotropin, Transfection, Blotting, Western, Gene Expression, Dimerization, 1-Phosphatidylinositol 4-Kinase, Electrophoretic Mobility Shift Assay, GTP-Binding Protein alpha Subunits, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Oncogene Protein v-akt, Rats, Paired Box Transcription Factors

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