1. Regulated Phosphosignaling Associated with Breast Cancer Subtypes and Druggability*
- Author
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Li Ding, Michael C. Wendl, Tina Primeau, Christopher R. Kinsinger, R. Reid Townsend, Adam D. Scott, Kuan-lin Huang, Shunqiang Li, Sherri R. Davies, Kimberly J. Johnson, David Fenyö, Joshua F. McMichael, Yuqian Gao, Yi-Ting Wang, Samuel H. Payne, Yige Wu, Jason M. Held, Arvin C. Dar, Mehdi Mesri, Kelly V. Ruggles, Steven A. Carr, Song Cao, Tao Liu, Henry Rodriguez, Feng Chen, and Matthew J. Ellis
- Subjects
Cell signaling ,Druggability ,AKT1 ,Breast Neoplasms ,Biochemistry ,Analytical Chemistry ,03 medical and health sciences ,Breast cancer ,Cyclin-dependent kinase ,medicine ,Humans ,Phosphorylation ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,Kinase ,Research ,030302 biochemistry & molecular biology ,Cancer ,medicine.disease ,Cancer research ,biology.protein ,Female ,Protein Kinases ,Signal Transduction - 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 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.
- Published
- 2019