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Overlap in signaling between Smoothened and the α subunit of the heterotrimeric G protein G(13)

The Hedgehog family of morphogens has long been known to utilize, through the 7-transmembrane protein Smoothened (Smo), the heterotrimeric G protein G(i) in both canonical and noncanonical forms of signaling. Other G proteins, while not specifically utilized by Smo, may nonetheless provide access to...

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Autores principales: Guo, Xueshui, Riobo-Del Galdo, Natalia A., Kim, Eun Ji, Grant, Gregory R., Manning, David R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953476/
https://www.ncbi.nlm.nih.gov/pubmed/29763457
http://dx.doi.org/10.1371/journal.pone.0197442
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author Guo, Xueshui
Riobo-Del Galdo, Natalia A.
Kim, Eun Ji
Grant, Gregory R.
Manning, David R.
author_facet Guo, Xueshui
Riobo-Del Galdo, Natalia A.
Kim, Eun Ji
Grant, Gregory R.
Manning, David R.
author_sort Guo, Xueshui
collection PubMed
description The Hedgehog family of morphogens has long been known to utilize, through the 7-transmembrane protein Smoothened (Smo), the heterotrimeric G protein G(i) in both canonical and noncanonical forms of signaling. Other G proteins, while not specifically utilized by Smo, may nonetheless provide access to some of the events controlled by it. We reported several years ago that the G protein G(13) activates one or more forms of the Gli family of transcription factors. While the Gli transcription factors are well known targets for Smo, the uncertain mechanism of activation by G(13) and the identity of the targeted Gli(s) limited predictions as to the extent to which G(13) might mimic Smo’s actions. We evaluate here the potential for overlap in G(13) and Smo signaling using C3H10T1/2 and 3T3-L1 cells as models of osteogenesis and adipogenesis, respectively. We find in C3H10T1/2 cells that a constitutively active form of Gα(13) (Gα(13)QL) increases Gli1 mRNA, as does a constitutively active form of Smo (SmoA1). We find as well that Gα(13)QL induces alkaline phosphatase activity, a marker of osteogenesis, albeit the induction is far less substantial than that achieved by SmoA1. In 3T3-L1 cells both Gα(13)QL and SmoA1 markedly suppress adipogenic differentiation as determined by triglyceride accumulation. RNA sequencing reveals that Gα(13)QL and SmoA1 regulate many of the same genes but that quantitative and qualitative differences exist. Differences also exist, we find, between SmoA1 and purmorphamine, an agonist for Smo. Therefore, while comparisons of constitutively active proteins are informative, extrapolations to the setting of agonists require care.
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spelling pubmed-59534762018-05-25 Overlap in signaling between Smoothened and the α subunit of the heterotrimeric G protein G(13) Guo, Xueshui Riobo-Del Galdo, Natalia A. Kim, Eun Ji Grant, Gregory R. Manning, David R. PLoS One Research Article The Hedgehog family of morphogens has long been known to utilize, through the 7-transmembrane protein Smoothened (Smo), the heterotrimeric G protein G(i) in both canonical and noncanonical forms of signaling. Other G proteins, while not specifically utilized by Smo, may nonetheless provide access to some of the events controlled by it. We reported several years ago that the G protein G(13) activates one or more forms of the Gli family of transcription factors. While the Gli transcription factors are well known targets for Smo, the uncertain mechanism of activation by G(13) and the identity of the targeted Gli(s) limited predictions as to the extent to which G(13) might mimic Smo’s actions. We evaluate here the potential for overlap in G(13) and Smo signaling using C3H10T1/2 and 3T3-L1 cells as models of osteogenesis and adipogenesis, respectively. We find in C3H10T1/2 cells that a constitutively active form of Gα(13) (Gα(13)QL) increases Gli1 mRNA, as does a constitutively active form of Smo (SmoA1). We find as well that Gα(13)QL induces alkaline phosphatase activity, a marker of osteogenesis, albeit the induction is far less substantial than that achieved by SmoA1. In 3T3-L1 cells both Gα(13)QL and SmoA1 markedly suppress adipogenic differentiation as determined by triglyceride accumulation. RNA sequencing reveals that Gα(13)QL and SmoA1 regulate many of the same genes but that quantitative and qualitative differences exist. Differences also exist, we find, between SmoA1 and purmorphamine, an agonist for Smo. Therefore, while comparisons of constitutively active proteins are informative, extrapolations to the setting of agonists require care. Public Library of Science 2018-05-15 /pmc/articles/PMC5953476/ /pubmed/29763457 http://dx.doi.org/10.1371/journal.pone.0197442 Text en © 2018 Guo et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Guo, Xueshui
Riobo-Del Galdo, Natalia A.
Kim, Eun Ji
Grant, Gregory R.
Manning, David R.
Overlap in signaling between Smoothened and the α subunit of the heterotrimeric G protein G(13)
title Overlap in signaling between Smoothened and the α subunit of the heterotrimeric G protein G(13)
title_full Overlap in signaling between Smoothened and the α subunit of the heterotrimeric G protein G(13)
title_fullStr Overlap in signaling between Smoothened and the α subunit of the heterotrimeric G protein G(13)
title_full_unstemmed Overlap in signaling between Smoothened and the α subunit of the heterotrimeric G protein G(13)
title_short Overlap in signaling between Smoothened and the α subunit of the heterotrimeric G protein G(13)
title_sort overlap in signaling between smoothened and the α subunit of the heterotrimeric g protein g(13)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953476/
https://www.ncbi.nlm.nih.gov/pubmed/29763457
http://dx.doi.org/10.1371/journal.pone.0197442
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