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Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)

Individuals with poor postnatal growth are at risk for cardiovascular and metabolic problems as adults. Here we show that disruption of the molecular scaffold Kinase Suppressor of Ras 2 (KSR2) causes selective inhibition of hepatic GH signaling in neonatal mice with impaired expression of IGF-1 and...

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Autores principales: Guo, Lili, Costanzo-Garvey, Diane L., Smith, Deandra R., Zavorka, Megan E., Venable-Kang, Megan, MacDonald, Richard G., Lewis, Robert E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999994/
https://www.ncbi.nlm.nih.gov/pubmed/27561547
http://dx.doi.org/10.1038/srep32093
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author Guo, Lili
Costanzo-Garvey, Diane L.
Smith, Deandra R.
Zavorka, Megan E.
Venable-Kang, Megan
MacDonald, Richard G.
Lewis, Robert E.
author_facet Guo, Lili
Costanzo-Garvey, Diane L.
Smith, Deandra R.
Zavorka, Megan E.
Venable-Kang, Megan
MacDonald, Richard G.
Lewis, Robert E.
author_sort Guo, Lili
collection PubMed
description Individuals with poor postnatal growth are at risk for cardiovascular and metabolic problems as adults. Here we show that disruption of the molecular scaffold Kinase Suppressor of Ras 2 (KSR2) causes selective inhibition of hepatic GH signaling in neonatal mice with impaired expression of IGF-1 and IGFBP3. ksr2(−/−) mice are normal size at birth but show a marked increase in FGF21 accompanied by reduced body mass, shortened body length, and reduced bone mineral density (BMD) and content (BMC) first evident during postnatal development. However, disrupting FGF21 in ksr2(−/−) mice does not normalize mass, length, or bone density and content in fgf21(−/−)ksr2(−/−) mice. Body length, BMC and BMD, but not body mass, are rescued by infection of two-day-old ksr2(−/−) mice with a recombinant adenovirus encoding human IGF-1. Relative to wild-type mice, GH injections reveal a significant reduction in JAK2 and STAT5 phosphorylation in liver, but not in skeletal muscle, of ksr2(−/−) mice. However, primary hepatocytes isolated from ksr2(−/−) mice show no reduction in GH-stimulated STAT5 phosphorylation. These data indicate that KSR2 functions in a cell non-autonomous fashion to regulate GH-stimulated IGF-1 expression in the liver of neonatal mice, which plays a key role in the development of body length.
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spelling pubmed-49999942016-09-07 Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2) Guo, Lili Costanzo-Garvey, Diane L. Smith, Deandra R. Zavorka, Megan E. Venable-Kang, Megan MacDonald, Richard G. Lewis, Robert E. Sci Rep Article Individuals with poor postnatal growth are at risk for cardiovascular and metabolic problems as adults. Here we show that disruption of the molecular scaffold Kinase Suppressor of Ras 2 (KSR2) causes selective inhibition of hepatic GH signaling in neonatal mice with impaired expression of IGF-1 and IGFBP3. ksr2(−/−) mice are normal size at birth but show a marked increase in FGF21 accompanied by reduced body mass, shortened body length, and reduced bone mineral density (BMD) and content (BMC) first evident during postnatal development. However, disrupting FGF21 in ksr2(−/−) mice does not normalize mass, length, or bone density and content in fgf21(−/−)ksr2(−/−) mice. Body length, BMC and BMD, but not body mass, are rescued by infection of two-day-old ksr2(−/−) mice with a recombinant adenovirus encoding human IGF-1. Relative to wild-type mice, GH injections reveal a significant reduction in JAK2 and STAT5 phosphorylation in liver, but not in skeletal muscle, of ksr2(−/−) mice. However, primary hepatocytes isolated from ksr2(−/−) mice show no reduction in GH-stimulated STAT5 phosphorylation. These data indicate that KSR2 functions in a cell non-autonomous fashion to regulate GH-stimulated IGF-1 expression in the liver of neonatal mice, which plays a key role in the development of body length. Nature Publishing Group 2016-08-26 /pmc/articles/PMC4999994/ /pubmed/27561547 http://dx.doi.org/10.1038/srep32093 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Guo, Lili
Costanzo-Garvey, Diane L.
Smith, Deandra R.
Zavorka, Megan E.
Venable-Kang, Megan
MacDonald, Richard G.
Lewis, Robert E.
Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)
title Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)
title_full Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)
title_fullStr Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)
title_full_unstemmed Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)
title_short Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)
title_sort cell non-autonomous regulation of hepatic igf-1 and neonatal growth by kinase suppressor of ras 2 (ksr2)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999994/
https://www.ncbi.nlm.nih.gov/pubmed/27561547
http://dx.doi.org/10.1038/srep32093
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