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Nat Commun. 2014 Sep 23;5:4961. doi: 10.1038/ncomms5961.

Activation of diverse signalling pathways by oncogenic PIK3CA mutations.

Author information

1
McKusick-Nathans Institute of Genetic Medicine and Department of Biological Chemistry, Johns Hopkins University School of Medicine, 733 North Broadway, BRB 527, Baltimore, Maryland 21205, USA.
2
1] Institute of Bioinformatics, International Tech Park, Bangalore 560066, India [2] Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 690 525, India.
3
1] Institute of Bioinformatics, International Tech Park, Bangalore 560066, India [2] Manipal University, Manipal 576104, India.
4
Institute of Bioinformatics, International Tech Park, Bangalore 560066, India.
5
Ludwig Center and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
6
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
7
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
8
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
9
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
10
Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
11
1] McKusick-Nathans Institute of Genetic Medicine and Department of Biological Chemistry, Johns Hopkins University School of Medicine, 733 North Broadway, BRB 527, Baltimore, Maryland 21205, USA [2] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA [3] Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.

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.

PMID:
25247763
PMCID:
PMC4210192
DOI:
10.1038/ncomms5961
[Indexed for MEDLINE]
Free PMC Article

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