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TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function

While TGFβ signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFβ appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFβ pathway, we first generated mouse models of neoplastic disease with TGFβ receptor deficiencies. Th...

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Autores principales: Principe, D R, Diaz, A M, Torres, C, Mangan, R J, DeCant, B, McKinney, R, Tsao, M-S, Lowy, A, Munshi, H G, Jung, B, Grippo, P J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537609/
https://www.ncbi.nlm.nih.gov/pubmed/28368414
http://dx.doi.org/10.1038/onc.2016.500
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author Principe, D R
Diaz, A M
Torres, C
Mangan, R J
DeCant, B
McKinney, R
Tsao, M-S
Lowy, A
Munshi, H G
Jung, B
Grippo, P J
author_facet Principe, D R
Diaz, A M
Torres, C
Mangan, R J
DeCant, B
McKinney, R
Tsao, M-S
Lowy, A
Munshi, H G
Jung, B
Grippo, P J
author_sort Principe, D R
collection PubMed
description While TGFβ signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFβ appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFβ pathway, we first generated mouse models of neoplastic disease with TGFβ receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGFβ led to rapid and sustained TGFBR1-dependent ERK phosphorylation in benign pancreatic duct cells. Similar to results that our group has published in colon cancer cells, inhibition of ERK phosphorylation in duct cells mitigated TGFβ-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGFβ-induced EMT. These observations suggest that ERK is a key factor in growth suppressive TGFβ signals, yet may also contribute to detrimental TGFβ signaling such as EMT. In neoplastic PanIN cells, pERK was not necessary for either TGFβ-induced pSMAD2 phosphorylation or CDK2 repression, but was required for upregulation of p21 and EMT indicating a partial divergence between TGFβ and MEK/ERK in early carcinogenesis. In cancer cells, pERK had no effect on TGFβ-induced upregulation of pSMAD2 and p21, suggesting the two pathways have completely diverged with respect to the cell cycle. Furthermore, inhibition of pERK both reduced levels of CDK2 and prevented EMT independent of exogenous TGFβ, consistent with most observations identifying pERK as a tumor promoter. Combined, these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGFβ-mediated cell cycle arrest, yet remains critical for the pathological, EMT-inducing arm of TGFβ signaling.
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spelling pubmed-55376092017-09-20 TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function Principe, D R Diaz, A M Torres, C Mangan, R J DeCant, B McKinney, R Tsao, M-S Lowy, A Munshi, H G Jung, B Grippo, P J Oncogene Original Article While TGFβ signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFβ appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFβ pathway, we first generated mouse models of neoplastic disease with TGFβ receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGFβ led to rapid and sustained TGFBR1-dependent ERK phosphorylation in benign pancreatic duct cells. Similar to results that our group has published in colon cancer cells, inhibition of ERK phosphorylation in duct cells mitigated TGFβ-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGFβ-induced EMT. These observations suggest that ERK is a key factor in growth suppressive TGFβ signals, yet may also contribute to detrimental TGFβ signaling such as EMT. In neoplastic PanIN cells, pERK was not necessary for either TGFβ-induced pSMAD2 phosphorylation or CDK2 repression, but was required for upregulation of p21 and EMT indicating a partial divergence between TGFβ and MEK/ERK in early carcinogenesis. In cancer cells, pERK had no effect on TGFβ-induced upregulation of pSMAD2 and p21, suggesting the two pathways have completely diverged with respect to the cell cycle. Furthermore, inhibition of pERK both reduced levels of CDK2 and prevented EMT independent of exogenous TGFβ, consistent with most observations identifying pERK as a tumor promoter. Combined, these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGFβ-mediated cell cycle arrest, yet remains critical for the pathological, EMT-inducing arm of TGFβ signaling. Nature Publishing Group 2017-07-27 2017-04-03 /pmc/articles/PMC5537609/ /pubmed/28368414 http://dx.doi.org/10.1038/onc.2016.500 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 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-nc-nd/4.0/
spellingShingle Original Article
Principe, D R
Diaz, A M
Torres, C
Mangan, R J
DeCant, B
McKinney, R
Tsao, M-S
Lowy, A
Munshi, H G
Jung, B
Grippo, P J
TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function
title TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function
title_full TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function
title_fullStr TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function
title_full_unstemmed TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function
title_short TGFβ engages MEK/ERK to differentially regulate benign and malignant pancreas cell function
title_sort tgfβ engages mek/erk to differentially regulate benign and malignant pancreas cell function
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537609/
https://www.ncbi.nlm.nih.gov/pubmed/28368414
http://dx.doi.org/10.1038/onc.2016.500
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