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Regulated Phosphosignaling Associated with Breast Cancer Subtypes and Druggability.
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.
Afiliación
  • Huang KL; ‡Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; §Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029; ¶Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 100
  • Wu Y; **Department of Medicine, Washington University in St. Louis, MO 63108; ‡‡McDonnell Genome Institute, Washington University in St. Louis, MO 63108.
  • Primeau T; ‡‡McDonnell Genome Institute, Washington University in St. Louis, MO 63108.
  • Wang YT; §§§Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352.
  • Gao Y; §§§Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352.
  • McMichael JF; **Department of Medicine, Washington University in St. Louis, MO 63108.
  • Scott AD; **Department of Medicine, Washington University in St. Louis, MO 63108; ‡‡McDonnell Genome Institute, Washington University in St. Louis, MO 63108.
  • Cao S; **Department of Medicine, Washington University in St. Louis, MO 63108; ‡‡McDonnell Genome Institute, Washington University in St. Louis, MO 63108.
  • Wendl MC; ‡‡McDonnell Genome Institute, Washington University in St. Louis, MO 63108; §§Department of Genetics, Washington University in St. Louis, MO 63108; ¶¶Department of Mathematics, Washington University in St. Louis, MO 63108. Electronic address: lding@genome.wustl.edu.
  • Johnson KJ; ‖‖Siteman Cancer Center, Washington University in St. Louis, MO 63108; ‡‡‡Brown School of Social Work, Washington University in St. Louis, MO 63108.
  • Ruggles K; ¶¶¶Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, NY 10016.
  • Held J; **Department of Medicine, Washington University in St. Louis, MO 63108; ‖‖Siteman Cancer Center, Washington University in St. Louis, MO 63108.
  • Payne SH; §§§Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352.
  • Davies S; **Department of Medicine, Washington University in St. Louis, MO 63108; ‖‖Siteman Cancer Center, Washington University in St. Louis, MO 63108.
  • Dar A; ‖Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
  • Kinsinger CR; ‖‖‖National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
  • Mesri M; ‖‖‖National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
  • Rodriguez H; ‖‖‖National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
  • Ellis MJ; ‡‡‡‡Dan L. Duncan Cancer Center & Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
  • Townsend RR; **Department of Medicine, Washington University in St. Louis, MO 63108; ‖‖Siteman Cancer Center, Washington University in St. Louis, MO 63108.
  • Chen F; **Department of Medicine, Washington University in St. Louis, MO 63108; ‖‖Siteman Cancer Center, Washington University in St. Louis, MO 63108.
  • Fenyö D; ¶¶Department of Mathematics, Washington University in St. Louis, MO 63108.
  • Li S; **Department of Medicine, Washington University in St. Louis, MO 63108; ‖‖Siteman Cancer Center, Washington University in St. Louis, MO 63108.
  • Liu T; ‡‡McDonnell Genome Institute, Washington University in St. Louis, MO 63108.
  • Carr SA; §§§§The Broad Institute of MIT and Harvard, Cambridge, MA 02142.
  • Ding L; **Department of Medicine, Washington University in St. Louis, MO 63108; §§Department of Genetics, Washington University in St. Louis, MO 63108; ‖‖Siteman Cancer Center, Washington University in St. Louis, MO 63108.
Mol Cell Proteomics ; 18(8): 1630-1650, 2019 08.
Article en En | MEDLINE | ID: mdl-31196969
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Quinasas / Neoplasias de la Mama Tipo de estudio: Risk_factors_studies Límite: Female / Humans Idioma: En Revista: Mol Cell Proteomics Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Quinasas / Neoplasias de la Mama Tipo de estudio: Risk_factors_studies Límite: Female / Humans Idioma: En Revista: Mol Cell Proteomics Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos