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Activation of diverse signaling pathways by oncogenic PIK3CA mutations

The PIK3CA gene is frequently mutated in human cancers. Here we carry out a SILAC-based quantitative phosphoproteomic analysis using isogenic knockin cell lines containing ‘driver’ oncogenic mutations of PIK3CA to dissect the signaling mechanisms responsible for oncogenic phenotypes induced by mutan...

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Autores principales: Wu, Xinyan, Renuse, Santosh, Sahasrabuddhe, Nandini A., Zahari, Muhammad Saddiq, Chaerkady, Raghothama, Kim, Min-Sik, Nirujogi, Raja S., Mohseni, Morassa, Kumar, Praveen, Raju, Rajesh, Zhong, Jun, Yang, Jian, Neiswinger, Johnathan, Jeong, Jun-Seop, Newman, Robert, Powers, Maureen A., Somani, Babu Lal, Gabrielson, Edward, Sukumar, Saraswati, Stearns, Vered, Qian, Jiang, Zhu, Heng, Vogelstein, Bert, Park, Ben Ho, Pandey, Akhilesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210192/
https://www.ncbi.nlm.nih.gov/pubmed/25247763
http://dx.doi.org/10.1038/ncomms5961
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author Wu, Xinyan
Renuse, Santosh
Sahasrabuddhe, Nandini A.
Zahari, Muhammad Saddiq
Chaerkady, Raghothama
Kim, Min-Sik
Nirujogi, Raja S.
Mohseni, Morassa
Kumar, Praveen
Raju, Rajesh
Zhong, Jun
Yang, Jian
Neiswinger, Johnathan
Jeong, Jun-Seop
Newman, Robert
Powers, Maureen A.
Somani, Babu Lal
Gabrielson, Edward
Sukumar, Saraswati
Stearns, Vered
Qian, Jiang
Zhu, Heng
Vogelstein, Bert
Park, Ben Ho
Pandey, Akhilesh
author_facet Wu, Xinyan
Renuse, Santosh
Sahasrabuddhe, Nandini A.
Zahari, Muhammad Saddiq
Chaerkady, Raghothama
Kim, Min-Sik
Nirujogi, Raja S.
Mohseni, Morassa
Kumar, Praveen
Raju, Rajesh
Zhong, Jun
Yang, Jian
Neiswinger, Johnathan
Jeong, Jun-Seop
Newman, Robert
Powers, Maureen A.
Somani, Babu Lal
Gabrielson, Edward
Sukumar, Saraswati
Stearns, Vered
Qian, Jiang
Zhu, Heng
Vogelstein, Bert
Park, Ben Ho
Pandey, Akhilesh
author_sort Wu, Xinyan
collection PubMed
description The PIK3CA gene is frequently mutated in human cancers. Here we carry out a SILAC-based quantitative phosphoproteomic analysis using isogenic knockin cell lines containing ‘driver’ oncogenic mutations of PIK3CA to dissect the signaling mechanisms responsible for oncogenic phenotypes induced by mutant PIK3CA. From 8,075 unique phosphopeptides identified, we observe that aberrant activation of PI3K pathway leads to increased phosphorylation of a surprisingly wide variety of kinases and downstream signaling networks. Here, by integrating phosphoproteomic data with human protein microarray-based AKT1 kinase assays, we discover and validate six novel AKT1 substrates, including cortactin. Through mutagenesis studies, we demonstrate that phosphorylation of cortactin by AKT1 is important for mutant PI3K enhanced cell migration and invasion. Our study describes a quantitative and global approach for identifying mutation-specific signaling events and for discovering novel signaling molecules as readouts of pathway activation or potential therapeutic targets.
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spelling pubmed-42101922015-03-23 Activation of diverse signaling pathways by oncogenic PIK3CA mutations Wu, Xinyan Renuse, Santosh Sahasrabuddhe, Nandini A. Zahari, Muhammad Saddiq Chaerkady, Raghothama Kim, Min-Sik Nirujogi, Raja S. Mohseni, Morassa Kumar, Praveen Raju, Rajesh Zhong, Jun Yang, Jian Neiswinger, Johnathan Jeong, Jun-Seop Newman, Robert Powers, Maureen A. Somani, Babu Lal Gabrielson, Edward Sukumar, Saraswati Stearns, Vered Qian, Jiang Zhu, Heng Vogelstein, Bert Park, Ben Ho Pandey, Akhilesh Nat Commun Article The PIK3CA gene is frequently mutated in human cancers. Here we carry out a SILAC-based quantitative phosphoproteomic analysis using isogenic knockin cell lines containing ‘driver’ oncogenic mutations of PIK3CA to dissect the signaling mechanisms responsible for oncogenic phenotypes induced by mutant PIK3CA. From 8,075 unique phosphopeptides identified, we observe that aberrant activation of PI3K pathway leads to increased phosphorylation of a surprisingly wide variety of kinases and downstream signaling networks. Here, by integrating phosphoproteomic data with human protein microarray-based AKT1 kinase assays, we discover and validate six novel AKT1 substrates, including cortactin. Through mutagenesis studies, we demonstrate that phosphorylation of cortactin by AKT1 is important for mutant PI3K enhanced cell migration and invasion. Our study describes a quantitative and global approach for identifying mutation-specific signaling events and for discovering novel signaling molecules as readouts of pathway activation or potential therapeutic targets. 2014-09-23 /pmc/articles/PMC4210192/ /pubmed/25247763 http://dx.doi.org/10.1038/ncomms5961 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wu, Xinyan
Renuse, Santosh
Sahasrabuddhe, Nandini A.
Zahari, Muhammad Saddiq
Chaerkady, Raghothama
Kim, Min-Sik
Nirujogi, Raja S.
Mohseni, Morassa
Kumar, Praveen
Raju, Rajesh
Zhong, Jun
Yang, Jian
Neiswinger, Johnathan
Jeong, Jun-Seop
Newman, Robert
Powers, Maureen A.
Somani, Babu Lal
Gabrielson, Edward
Sukumar, Saraswati
Stearns, Vered
Qian, Jiang
Zhu, Heng
Vogelstein, Bert
Park, Ben Ho
Pandey, Akhilesh
Activation of diverse signaling pathways by oncogenic PIK3CA mutations
title Activation of diverse signaling pathways by oncogenic PIK3CA mutations
title_full Activation of diverse signaling pathways by oncogenic PIK3CA mutations
title_fullStr Activation of diverse signaling pathways by oncogenic PIK3CA mutations
title_full_unstemmed Activation of diverse signaling pathways by oncogenic PIK3CA mutations
title_short Activation of diverse signaling pathways by oncogenic PIK3CA mutations
title_sort activation of diverse signaling pathways by oncogenic pik3ca mutations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210192/
https://www.ncbi.nlm.nih.gov/pubmed/25247763
http://dx.doi.org/10.1038/ncomms5961
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