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Mol Cell Proteomics DOI:10.1074/mcp.RA118.001243

Regulated Phosphosignaling Associated with Breast Cancer Subtypes and Druggability.

Publication TypeJournal Article
Year of Publication2019
AuthorsHuang, K-lin, Wu, Y, Primeau, T, Wang, Y-T, Gao, Y, McMichael, JF, Scott, AD, Cao, S, Wendl, MC, Johnson, KJ, Ruggles, K, Held, J, Payne, SH, Davies, SR, Dar, A, Kinsinger, CR, Mesri, M, Rodriguez, H, Ellis, MJ, R Townsend, R, Chen, F, Fenyö, D, Li, S, Liu, T, Carr, SA, Ding, L
JournalMol Cell Proteomics
Date Published2019 Jun 13
ISSN1535-9484
Abstract

Aberrant phospho-signaling is a hallmark of cancer. We investigated kinase-substrate regulation of 33,239 phosphorylation sites (phosphosites) in 77 breast tumors and 24 breast cancer xenografts. Our search discovered 2,134 quantitatively-correlated kinase-phosphosite pairs, enriching for and extending experimental or binding-motif predictions. Among the 91 kinases with auto-phosphorylation, elevated EGFR, ERBB2, PRKG1, and WNK1 phosphosignaling were enriched in basal, HER2-E, Luminal A, and Luminal B breast cancers, respectively, revealing subtype-specific regulation. CDKs, MAPKs, and ataxia-telangiectasia proteins were dominant, master regulators of substrate-phosphorylation, whose activities are not captured by genomic evidence. We unveiled phospho-signaling and druggable targets from 113 kinase-substrate pairs and cascades downstream of kinases, including AKT1, BRAF and EGFR. We further identified kinase-substrate-pairs associated with clinical or immune signatures and experimentally validated activated phosphosites of ERBB2, EIF4EBP1, and EGFR. Overall, kinase-substrate regulation revealed by the largest unbiased global phosphorylation data to date connects driver events to their signaling effects.

DOI10.1074/mcp.RA118.001243
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31196969?dopt=Abstract

Alternate JournalMol. Cell Proteomics
PubMed ID31196969