Regulated phosphosignaling associated with breast cancer subtypes and druggability

Kuan lin Huang, Yige Wu, Tina Primeau, Yi Ting Wang, Yuqian Gao, Joshua F. McMichael, Adam D. Scott, Song Cao, Michael C. Wendl, Kimberly J. Johnson, Kelly Ruggles, Jason Held, Samuel H. Payne, Sherri Davies, Arvin Dar, Christopher R. Kinsinger, Mehdi Mesri, Henry Rodriguez, Matthew J. Ellis, R. Reid TownsendFeng Chen, David Fenyö, Shunqiang Li, Tao Liu, Steven A. Carr, Li Ding

Research output: Contribution to journalArticlepeer-review

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 2134 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 phosphosignaling 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.

Original languageEnglish
Pages (from-to)1630-1650
Number of pages21
JournalMolecular and Cellular Proteomics
Volume18
Issue number8
DOIs
StatePublished - 2019

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