Cargando…

Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity

Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signalin...

Descripción completa

Detalles Bibliográficos
Autores principales: Ma, Gary S., Lopez-Sanchez, Inmaculada, Aznar, Nicolas, Kalogriopoulos, Nicholas, Pedram, Shabnam, Midde, Krishna, Ciaraldi, Theodore P., Henry, Robert R., Ghosh, Pradipta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642855/
https://www.ncbi.nlm.nih.gov/pubmed/26378251
http://dx.doi.org/10.1091/mbc.E15-08-0553
_version_ 1782400431293464576
author Ma, Gary S.
Lopez-Sanchez, Inmaculada
Aznar, Nicolas
Kalogriopoulos, Nicholas
Pedram, Shabnam
Midde, Krishna
Ciaraldi, Theodore P.
Henry, Robert R.
Ghosh, Pradipta
author_facet Ma, Gary S.
Lopez-Sanchez, Inmaculada
Aznar, Nicolas
Kalogriopoulos, Nicholas
Pedram, Shabnam
Midde, Krishna
Ciaraldi, Theodore P.
Henry, Robert R.
Ghosh, Pradipta
author_sort Ma, Gary S.
collection PubMed
description Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles.
format Online
Article
Text
id pubmed-4642855
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-46428552016-01-30 Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity Ma, Gary S. Lopez-Sanchez, Inmaculada Aznar, Nicolas Kalogriopoulos, Nicholas Pedram, Shabnam Midde, Krishna Ciaraldi, Theodore P. Henry, Robert R. Ghosh, Pradipta Mol Biol Cell Articles Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles. The American Society for Cell Biology 2015-11-15 /pmc/articles/PMC4642855/ /pubmed/26378251 http://dx.doi.org/10.1091/mbc.E15-08-0553 Text en © 2015 Ma et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Ma, Gary S.
Lopez-Sanchez, Inmaculada
Aznar, Nicolas
Kalogriopoulos, Nicholas
Pedram, Shabnam
Midde, Krishna
Ciaraldi, Theodore P.
Henry, Robert R.
Ghosh, Pradipta
Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity
title Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity
title_full Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity
title_fullStr Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity
title_full_unstemmed Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity
title_short Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity
title_sort activation of g proteins by giv-gef is a pivot point for insulin resistance and sensitivity
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642855/
https://www.ncbi.nlm.nih.gov/pubmed/26378251
http://dx.doi.org/10.1091/mbc.E15-08-0553
work_keys_str_mv AT magarys activationofgproteinsbygivgefisapivotpointforinsulinresistanceandsensitivity
AT lopezsanchezinmaculada activationofgproteinsbygivgefisapivotpointforinsulinresistanceandsensitivity
AT aznarnicolas activationofgproteinsbygivgefisapivotpointforinsulinresistanceandsensitivity
AT kalogriopoulosnicholas activationofgproteinsbygivgefisapivotpointforinsulinresistanceandsensitivity
AT pedramshabnam activationofgproteinsbygivgefisapivotpointforinsulinresistanceandsensitivity
AT middekrishna activationofgproteinsbygivgefisapivotpointforinsulinresistanceandsensitivity
AT ciaralditheodorep activationofgproteinsbygivgefisapivotpointforinsulinresistanceandsensitivity
AT henryrobertr activationofgproteinsbygivgefisapivotpointforinsulinresistanceandsensitivity
AT ghoshpradipta activationofgproteinsbygivgefisapivotpointforinsulinresistanceandsensitivity