TY - JOUR
T1 - Regulated phosphosignaling associated with breast cancer subtypes and druggability
AU - Huang, Kuan lin
AU - Wu, Yige
AU - Primeau, Tina
AU - Wang, Yi Ting
AU - Gao, Yuqian
AU - McMichael, Joshua F.
AU - Scott, Adam D.
AU - Cao, Song
AU - Wendl, Michael C.
AU - Johnson, Kimberly J.
AU - Ruggles, Kelly
AU - Held, Jason
AU - Payne, Samuel H.
AU - Davies, Sherri
AU - Dar, Arvin
AU - Kinsinger, Christopher R.
AU - Mesri, Mehdi
AU - Rodriguez, Henry
AU - Ellis, Matthew J.
AU - Reid Townsend, R.
AU - Chen, Feng
AU - Fenyö, David
AU - Li, Shunqiang
AU - Liu, Tao
AU - Carr, Steven A.
AU - Ding, Li
N1 - Funding Information:
* This work was supported by the National Cancer Institute grants U24CA160035 to R.R.T. and M.J.E., U24CA210972 to D.F., L.D., and S.H.P., U24CA211006 to L.D. and R.G., and National Human Genome Research Institute grant U01HG006517 to L.D. The authors declare no competing financial interests. □S This article contains supplemental Figures and Tables. ‖‖‖‖ To whom correspondence may be addressed: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029. E-mail: kuan-lin.huang@mssm.edu. ¶¶¶¶ To whom correspondence may be addressed: Division of Oncology, Department of Medicine, McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108. E-mail: lding@genome.wustl.edu.
Funding Information:
We thank The Cancer Genome Atlas (cancer-genome.nih.gov) and CPTAC as the source of primary data and members of the CPTAC Research Network for helpful discussions. * This work was supported by the National Cancer Institute grants U24CA160035 to R.R.T. and M.J.E., U24CA210972 to D.F., L.D., and S.H.P., U24CA211006 to L.D. and R.G., and National Human Genome Research Institute grant U01HG006517 to L.D. The authors declare no competing financial interests.
Publisher Copyright:
© 2019 Huang et al.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070262578&partnerID=8YFLogxK
U2 - 10.1074/mcp.RA118.001243
DO - 10.1074/mcp.RA118.001243
M3 - Article
C2 - 31196969
AN - SCOPUS:85070262578
SN - 1535-9476
VL - 18
SP - 1630
EP - 1650
JO - Molecular and Cellular Proteomics
JF - Molecular and Cellular Proteomics
IS - 8
ER -