Activation of diverse signalling pathways by oncogenic ​PIK3CA mutations

Sahasrabuddhe, Nandini A and Kumar, Praveen (2014) Activation of diverse signalling pathways by oncogenic ​PIK3CA mutations. Nature Communications, 5. pp. 1-13. ISSN 2041-1723

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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.

Item Type: Article
Subjects: Research > Research Center - Health Sciences
Depositing User: KMC Manipal
Date Deposited: 12 Feb 2015 09:56
Last Modified: 12 Feb 2015 09:56

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