Regulated Phosphosignaling Associated with Breast Cancer Subtypes and Druggability[S]

• Published in: Molecular & cellular proteomics 2019-08, Vol.18 (8), p.1630-1650
• Main Authors: Huang, Kuan-lin, Wu, Yige, Primeau, Tina, Wang, Yi-Ting, Gao, Yuqian, McMichael, Joshua F., Scott, Adam D., Cao, Song, Wendl, Michael C., Johnson, Kimberly J., Ruggles, Kelly, Held, Jason, Payne, Samuel H., Davies, Sherri, Dar, Arvin, Kinsinger, Christopher R., Mesri, Mehdi, Rodriguez, Henry, Ellis, Matthew J., Townsend, R. Reid, Chen, Feng, Fenyö, David, Li, Shunqiang, Liu, Tao, Carr, Steven A., Ding, Li
• Format: Article
• Language: English
• Subjects: Bioinformatics; Breast cancer; Breast Neoplasms - metabolism; Drug targets; Female; Humans; Kinases; Mass Spectrometry; Phosphorylation; Protein Kinases - metabolism; Signal Transduction; Signaling Molecules
• ISSN: 1535-9476; 1535-9484
• DOI: 10.1074/mcp.RA118.001243

Phosphorylation of substrate proteins by kinases regulates signaling pathways and cellular mechanisms. Aberrant signaling is a hallmark of cancer. We investigated quantitative associations between kinase-substrate pairs of more than 30 thousand phosphorylation sites in breast tumors and xenografts, finding auto-phosphorylating kinases and kinase-substrate pairs associated with specific cancer subtypes, druggable targets, and ones that show clinically-related or immune signatures. Our study connects driver kinases to their signaling effects toward informing rational targeted treatments of individual breast tumors. [Display omitted] Highlights •Our search identifies 2,134 kinase-substrate phosphosite pairs in breast cancer.•CDKs and MAPKs are dominant regulators of trans substrate-phosphorylation.•Druggability, outcomes, and immune signatures related to kinase-substrates.•Experimentally validated activated phosphosites of ERBB2, EIF4EBP1, and EGFR. 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.