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; Akhilesh Pandey

doi:10.1038/ncomms5961

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 StearnsJiang Qian, Heng Zhu, Bert Vogelstein, Ben Ho Park, Akhilesh Pandey

Laboratory Medicine and Pathology

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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.

Original language	English (US)
Article number	4961
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5961
State	Published - 2014

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Wu, X., Renuse, S., Sahasrabuddhe, N. A., Zahari, M. S., Chaerkady, R., Kim, M. S., Nirujogi, R. S., Mohseni, M., Kumar, P., Raju, R., Zhong, J., Yang, J., Neiswinger, J., Jeong, J. S., Newman, R., Powers, M. A., Somani, B. L., Gabrielson, E., Sukumar, S., ... Pandey, A. (2014). Activation of diverse signalling pathways by oncogenic PIK3CA mutations. Nature communications, 5, [4961]. https://doi.org/10.1038/ncomms5961

Wu, X , Renuse, S, Sahasrabuddhe, NA, Zahari, MS, Chaerkady, R, Kim, MS, Nirujogi, RS, Mohseni, M, Kumar, P, Raju, R, Zhong, J, Yang, J, Neiswinger, J, Jeong, JS, Newman, R, Powers, MA, Somani, BL, Gabrielson, E, Sukumar, S, Stearns, V, Qian, J, Zhu, H, Vogelstein, B, Park, BH & Pandey, A 2014, 'Activation of diverse signalling pathways by oncogenic PIK3CA mutations', Nature communications, vol. 5, 4961. https://doi.org/10.1038/ncomms5961

@article{a04348a9d57645b28a75d084327ebd40,

title = "Activation of diverse signalling pathways by oncogenic PIK3CA mutations",

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.",

author = "Xinyan Wu and Santosh Renuse and Sahasrabuddhe, {Nandini A.} and Zahari, {Muhammad Saddiq} and Raghothama Chaerkady and Kim, {Min Sik} and Nirujogi, {Raja S.} and Morassa Mohseni and Praveen Kumar and Rajesh Raju and Jun Zhong and Jian Yang and Johnathan Neiswinger and Jeong, {Jun Seop} and Robert Newman and Powers, {Maureen A.} and Somani, {Babu Lal} and Edward Gabrielson and Saraswati Sukumar and Vered Stearns and Jiang Qian and Heng Zhu and Bert Vogelstein and Park, {Ben Ho} and Akhilesh Pandey",

note = "Funding Information: This study was supported by a Career Catalyst Award from the Susan G. Komen for the Cure foundation (KG100459 to X.W.), an NIH roadmap grant for Technology Centers of Networks and Pathways (U54GM103520 to A.P. and H.Z.), NCI{\textquoteright}s Clinical Proteomic Tumor Analysis Consortium initiative (U24CA160036 to A.P.), a contract (HHSN268201000032C to A.P.) from the National Heart, Lung and Blood Institute, a DOD Era of Hope Scholar Award (BC051652 to A.P.), the NIH SPORE (Specialized Programs of Research Excellence) in Gastrointestinal Cancer Grant (CA62924 to A.P. and B.V.), the Virginia and D.K. Ludwig Fund for Cancer Research (to B.V.), the Avon Foundation (B.H.P.), the Breast Cancer Research Foundation (B.H.P.) and an NIH RO1 grant (CA43460 to B.V.). We thank the Department of Biotechnology of the Government of India for research support to the Institute of Bioinformatics, Bangalore, India. S.R. is a recipient of Senior Research Fellowship from University Grants Commission, Government of India, and N.A.S. and R.S.N. are recipients of Senior Research Fellowship from Council of Scientific and Industrial Research, Government of India. We thank the Majlis Amanah Rakyat (MARA) of Government of Malaysia for the research fellowship to M.S.Z. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights reserved.",

year = "2014",

doi = "10.1038/ncomms5961",

language = "English (US)",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Activation of diverse signalling pathways by oncogenic PIK3CA mutations

AU - Wu, Xinyan

AU - Renuse, Santosh

AU - Sahasrabuddhe, Nandini A.

AU - Zahari, Muhammad Saddiq

AU - Chaerkady, Raghothama

AU - Kim, Min Sik

AU - Nirujogi, Raja S.

AU - Mohseni, Morassa

AU - Kumar, Praveen

AU - Raju, Rajesh

AU - Zhong, Jun

AU - Yang, Jian

AU - Neiswinger, Johnathan

AU - Jeong, Jun Seop

AU - Newman, Robert

AU - Powers, Maureen A.

AU - Somani, Babu Lal

AU - Gabrielson, Edward

AU - Sukumar, Saraswati

AU - Stearns, Vered

AU - Qian, Jiang

AU - Zhu, Heng

AU - Vogelstein, Bert

AU - Park, Ben Ho

AU - Pandey, Akhilesh

N1 - Funding Information: This study was supported by a Career Catalyst Award from the Susan G. Komen for the Cure foundation (KG100459 to X.W.), an NIH roadmap grant for Technology Centers of Networks and Pathways (U54GM103520 to A.P. and H.Z.), NCI’s Clinical Proteomic Tumor Analysis Consortium initiative (U24CA160036 to A.P.), a contract (HHSN268201000032C to A.P.) from the National Heart, Lung and Blood Institute, a DOD Era of Hope Scholar Award (BC051652 to A.P.), the NIH SPORE (Specialized Programs of Research Excellence) in Gastrointestinal Cancer Grant (CA62924 to A.P. and B.V.), the Virginia and D.K. Ludwig Fund for Cancer Research (to B.V.), the Avon Foundation (B.H.P.), the Breast Cancer Research Foundation (B.H.P.) and an NIH RO1 grant (CA43460 to B.V.). We thank the Department of Biotechnology of the Government of India for research support to the Institute of Bioinformatics, Bangalore, India. S.R. is a recipient of Senior Research Fellowship from University Grants Commission, Government of India, and N.A.S. and R.S.N. are recipients of Senior Research Fellowship from Council of Scientific and Industrial Research, Government of India. We thank the Majlis Amanah Rakyat (MARA) of Government of Malaysia for the research fellowship to M.S.Z. Publisher Copyright: © 2014 Macmillan Publishers Limited. All rights reserved.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms5961

DO - 10.1038/ncomms5961

M3 - Article

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SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 4961

ER -

Activation of diverse signalling pathways by oncogenic PIK3CA mutations

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