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Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion
Tumor progression to invasive carcinoma is associated with activation of SRC family kinase (SRC, YES, FYN) activity and loss of cellular cohesion. The hippo pathway-regulated cofactor YAP1 supports the tumorigenicity of RAS mutations but requires both inactivation of hippo signaling and YES-mediated...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683097/ https://www.ncbi.nlm.nih.gov/pubmed/26549256 http://dx.doi.org/10.1016/j.cub.2015.09.072 |
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author | Vlahov, Nikola Scrace, Simon Soto, Manuel Sarmiento Grawenda, Anna M. Bradley, Leanne Pankova, Daniela Papaspyropoulos, Angelos Yee, Karen S. Buffa, Francesca Goding, Colin R. Timpson, Paul Sibson, Nicola O’Neill, Eric |
author_facet | Vlahov, Nikola Scrace, Simon Soto, Manuel Sarmiento Grawenda, Anna M. Bradley, Leanne Pankova, Daniela Papaspyropoulos, Angelos Yee, Karen S. Buffa, Francesca Goding, Colin R. Timpson, Paul Sibson, Nicola O’Neill, Eric |
author_sort | Vlahov, Nikola |
collection | PubMed |
description | Tumor progression to invasive carcinoma is associated with activation of SRC family kinase (SRC, YES, FYN) activity and loss of cellular cohesion. The hippo pathway-regulated cofactor YAP1 supports the tumorigenicity of RAS mutations but requires both inactivation of hippo signaling and YES-mediated phosphorylation of YAP1 for oncogenic activity. Exactly how SRC kinases are activated and hippo signaling is lost in sporadic human malignancies remains unknown. Here, we provide evidence that hippo-mediated inhibition of YAP1 is lost upon promoter methylation of the RAS effector and hippo kinase scaffold RASSF1A. We find that RASSF1A promoter methylation reduces YAP phospho-S127, which derepresses YAP1, and actively supports YAP1 activation by switching RASSF1 transcription to the independently transcribed RASSF1C isoform that promotes Tyr kinase activity. Using affinity proteomics, proximity ligation, and real-time molecular visualization, we find that RASSF1C targets SRC/YES to epithelial cell-cell junctions and promotes tyrosine phosphorylation of E-cadherin, β-catenin, and YAP1. RASSF1A restricts SRC activity, preventing motility, invasion, and tumorigenesis in vitro and in vivo, with epigenetic inactivation correlating with increased inhibitory pY527-SRC in breast tumors. These data imply that distinct RASSF1 isoforms have opposing functions, which provide a biomarker for YAP1 activation and explain correlations of RASSF1 methylation with advanced invasive disease in humans. The ablation of epithelial integrity together with subsequent YAP1 nuclear localization allows transcriptional activation of β-catenin/TBX-YAP/TEAD target genes, including Myc, and an invasive phenotype. These findings define gene transcript switching as a tumor suppressor mechanism under epigenetic control. |
format | Online Article Text |
id | pubmed-4683097 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-46830972016-01-11 Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion Vlahov, Nikola Scrace, Simon Soto, Manuel Sarmiento Grawenda, Anna M. Bradley, Leanne Pankova, Daniela Papaspyropoulos, Angelos Yee, Karen S. Buffa, Francesca Goding, Colin R. Timpson, Paul Sibson, Nicola O’Neill, Eric Curr Biol Article Tumor progression to invasive carcinoma is associated with activation of SRC family kinase (SRC, YES, FYN) activity and loss of cellular cohesion. The hippo pathway-regulated cofactor YAP1 supports the tumorigenicity of RAS mutations but requires both inactivation of hippo signaling and YES-mediated phosphorylation of YAP1 for oncogenic activity. Exactly how SRC kinases are activated and hippo signaling is lost in sporadic human malignancies remains unknown. Here, we provide evidence that hippo-mediated inhibition of YAP1 is lost upon promoter methylation of the RAS effector and hippo kinase scaffold RASSF1A. We find that RASSF1A promoter methylation reduces YAP phospho-S127, which derepresses YAP1, and actively supports YAP1 activation by switching RASSF1 transcription to the independently transcribed RASSF1C isoform that promotes Tyr kinase activity. Using affinity proteomics, proximity ligation, and real-time molecular visualization, we find that RASSF1C targets SRC/YES to epithelial cell-cell junctions and promotes tyrosine phosphorylation of E-cadherin, β-catenin, and YAP1. RASSF1A restricts SRC activity, preventing motility, invasion, and tumorigenesis in vitro and in vivo, with epigenetic inactivation correlating with increased inhibitory pY527-SRC in breast tumors. These data imply that distinct RASSF1 isoforms have opposing functions, which provide a biomarker for YAP1 activation and explain correlations of RASSF1 methylation with advanced invasive disease in humans. The ablation of epithelial integrity together with subsequent YAP1 nuclear localization allows transcriptional activation of β-catenin/TBX-YAP/TEAD target genes, including Myc, and an invasive phenotype. These findings define gene transcript switching as a tumor suppressor mechanism under epigenetic control. Cell Press 2015-12-07 /pmc/articles/PMC4683097/ /pubmed/26549256 http://dx.doi.org/10.1016/j.cub.2015.09.072 Text en © 2015 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Vlahov, Nikola Scrace, Simon Soto, Manuel Sarmiento Grawenda, Anna M. Bradley, Leanne Pankova, Daniela Papaspyropoulos, Angelos Yee, Karen S. Buffa, Francesca Goding, Colin R. Timpson, Paul Sibson, Nicola O’Neill, Eric Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion |
title | Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion |
title_full | Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion |
title_fullStr | Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion |
title_full_unstemmed | Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion |
title_short | Alternate RASSF1 Transcripts Control SRC Activity, E-Cadherin Contacts, and YAP-Mediated Invasion |
title_sort | alternate rassf1 transcripts control src activity, e-cadherin contacts, and yap-mediated invasion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683097/ https://www.ncbi.nlm.nih.gov/pubmed/26549256 http://dx.doi.org/10.1016/j.cub.2015.09.072 |
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