Activation of diverse signalling pathways by oncogenic PIK3CA mutations.
Activation of diverse signalling pathways by oncogenic PIK3CA mutations.
Nature communications (2014-09-24)
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, Akhilesh Pandey
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.
