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Analysis of a cAMP regulated coactivator family reveals an alternative phosphorylation motif for AMPK family members

The second messenger cAMP stimulates cellular gene expression via the PKA-mediated phosphorylation of the transcription factor CREB and through dephosphorylation of the cAMP-responsive transcriptional coactivators (CRTCs). Under basal conditions, CRTCs are phosphorylated by members of the AMPK famil...

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Autores principales: Sonntag, Tim, Moresco, James J., Vaughan, Joan M., Matsumura, Shigenobu, Yates, John R., Montminy, Marc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325614/
https://www.ncbi.nlm.nih.gov/pubmed/28235073
http://dx.doi.org/10.1371/journal.pone.0173013
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author Sonntag, Tim
Moresco, James J.
Vaughan, Joan M.
Matsumura, Shigenobu
Yates, John R.
Montminy, Marc
author_facet Sonntag, Tim
Moresco, James J.
Vaughan, Joan M.
Matsumura, Shigenobu
Yates, John R.
Montminy, Marc
author_sort Sonntag, Tim
collection PubMed
description The second messenger cAMP stimulates cellular gene expression via the PKA-mediated phosphorylation of the transcription factor CREB and through dephosphorylation of the cAMP-responsive transcriptional coactivators (CRTCs). Under basal conditions, CRTCs are phosphorylated by members of the AMPK family of Ser/Thr kinases and sequestered in the cytoplasm via a phosphorylation-dependent association with 14-3-3 proteins. Increases in cAMP promote the dephosphorylation and nuclear translocation of CRTCs, where they bind to CREB and stimulate relevant target genes. Although they share considerable sequence homology, members of the CRTC family exert non-overlapping effects on cellular gene expression through as yet unidentified mechanisms. Here we show that the three CRTCs exhibit distinct patterns of 14-3-3 binding at three conserved sites corresponding to S70, S171, and S275 (in CRTC2). S171 functions as the gatekeeper site for 14-3-3 binding; it acts cooperatively with S275 in stabilizing this interaction following its phosphorylation by the cAMP-responsive SIK and the cAMP-nonresponsive MARK kinases. Although S171 contains a consensus recognition site for phosphorylation by AMPK family members, S70 and S275 carry variant motifs (MNTGGS(275)LPDL), lacking basic residues that are otherwise critical for SIK/MARK recognition as well as 14-3-3 binding. Correspondingly, the activity of these motifs differs between CRTC family members. As the variant (SLPDL) motif is present and apparently phosphorylated in other mammalian proteins, our studies suggest that the regulation of cellular targets by AMPK family members is more extensive than previously appreciated.
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spelling pubmed-53256142017-03-09 Analysis of a cAMP regulated coactivator family reveals an alternative phosphorylation motif for AMPK family members Sonntag, Tim Moresco, James J. Vaughan, Joan M. Matsumura, Shigenobu Yates, John R. Montminy, Marc PLoS One Research Article The second messenger cAMP stimulates cellular gene expression via the PKA-mediated phosphorylation of the transcription factor CREB and through dephosphorylation of the cAMP-responsive transcriptional coactivators (CRTCs). Under basal conditions, CRTCs are phosphorylated by members of the AMPK family of Ser/Thr kinases and sequestered in the cytoplasm via a phosphorylation-dependent association with 14-3-3 proteins. Increases in cAMP promote the dephosphorylation and nuclear translocation of CRTCs, where they bind to CREB and stimulate relevant target genes. Although they share considerable sequence homology, members of the CRTC family exert non-overlapping effects on cellular gene expression through as yet unidentified mechanisms. Here we show that the three CRTCs exhibit distinct patterns of 14-3-3 binding at three conserved sites corresponding to S70, S171, and S275 (in CRTC2). S171 functions as the gatekeeper site for 14-3-3 binding; it acts cooperatively with S275 in stabilizing this interaction following its phosphorylation by the cAMP-responsive SIK and the cAMP-nonresponsive MARK kinases. Although S171 contains a consensus recognition site for phosphorylation by AMPK family members, S70 and S275 carry variant motifs (MNTGGS(275)LPDL), lacking basic residues that are otherwise critical for SIK/MARK recognition as well as 14-3-3 binding. Correspondingly, the activity of these motifs differs between CRTC family members. As the variant (SLPDL) motif is present and apparently phosphorylated in other mammalian proteins, our studies suggest that the regulation of cellular targets by AMPK family members is more extensive than previously appreciated. Public Library of Science 2017-02-24 /pmc/articles/PMC5325614/ /pubmed/28235073 http://dx.doi.org/10.1371/journal.pone.0173013 Text en © 2017 Sonntag 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
Sonntag, Tim
Moresco, James J.
Vaughan, Joan M.
Matsumura, Shigenobu
Yates, John R.
Montminy, Marc
Analysis of a cAMP regulated coactivator family reveals an alternative phosphorylation motif for AMPK family members
title Analysis of a cAMP regulated coactivator family reveals an alternative phosphorylation motif for AMPK family members
title_full Analysis of a cAMP regulated coactivator family reveals an alternative phosphorylation motif for AMPK family members
title_fullStr Analysis of a cAMP regulated coactivator family reveals an alternative phosphorylation motif for AMPK family members
title_full_unstemmed Analysis of a cAMP regulated coactivator family reveals an alternative phosphorylation motif for AMPK family members
title_short Analysis of a cAMP regulated coactivator family reveals an alternative phosphorylation motif for AMPK family members
title_sort analysis of a camp regulated coactivator family reveals an alternative phosphorylation motif for ampk family members
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325614/
https://www.ncbi.nlm.nih.gov/pubmed/28235073
http://dx.doi.org/10.1371/journal.pone.0173013
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