Activation of diverse signalling pathways by oncogenic PIK3CA mutations

Xinyan Wu, Santosh Renuse, Nandini A. Sahasrabuddhe, Muhammad Saddiq Zahari, Raghothama Chaerkady, Min-Sik Kim, Raja S. Nirujogi, Morassa Mohseni, Praveen Kumar, Rajesh Raju, Jun Zhong, Jian Yang, Johnathan Neiswinger, Jun-Seop Jeong, Robert Newman, Maureen A. Powers, Babu Lal Somani, Edward Gabrielson, Saraswati Sukumar, Vered Stearns, Jiang Qian, Heng Zhu, Bert Vogelstein, Ben Ho Park () and Akhilesh Pandey ()
Additional contact information
Xinyan Wu: Johns Hopkins University School of Medicine, 733 North Broadway, BRB 527, Baltimore, Maryland 21205, USA
Santosh Renuse: Institute of Bioinformatics
Nandini A. Sahasrabuddhe: Institute of Bioinformatics
Muhammad Saddiq Zahari: Johns Hopkins University School of Medicine, 733 North Broadway, BRB 527, Baltimore, Maryland 21205, USA
Raghothama Chaerkady: Johns Hopkins University School of Medicine, 733 North Broadway, BRB 527, Baltimore, Maryland 21205, USA
Min-Sik Kim: Johns Hopkins University School of Medicine, 733 North Broadway, BRB 527, Baltimore, Maryland 21205, USA
Raja S. Nirujogi: Institute of Bioinformatics
Morassa Mohseni: Johns Hopkins University School of Medicine, 733 North Broadway, BRB 527, Baltimore, Maryland 21205, USA
Praveen Kumar: Institute of Bioinformatics
Rajesh Raju: Institute of Bioinformatics
Jun Zhong: Johns Hopkins University School of Medicine, 733 North Broadway, BRB 527, Baltimore, Maryland 21205, USA
Jian Yang: Ludwig Center and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine
Johnathan Neiswinger: Johns Hopkins University School of Medicine
Jun-Seop Jeong: Johns Hopkins University School of Medicine
Robert Newman: Johns Hopkins University School of Medicine
Maureen A. Powers: Emory University School of Medicine
Babu Lal Somani: Institute of Bioinformatics
Edward Gabrielson: Johns Hopkins University School of Medicine
Saraswati Sukumar: Johns Hopkins University School of Medicine
Vered Stearns: Johns Hopkins University School of Medicine
Jiang Qian: Wilmer Eye Institute, Johns Hopkins University School of Medicine
Heng Zhu: Johns Hopkins University School of Medicine
Bert Vogelstein: Ludwig Center and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine
Ben Ho Park: Johns Hopkins University School of Medicine
Akhilesh Pandey: Johns Hopkins University School of Medicine, 733 North Broadway, BRB 527, Baltimore, Maryland 21205, USA

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract 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 signalling 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 signalling 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 signalling events and for discovering novel signalling molecules as readouts of pathway activation or potential therapeutic targets.

Date: 2014
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DOI: 10.1038/ncomms5961

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