title: Context Specificity in Causal Signaling Networks Revealed by Phosphoprotein Profiling.
abstract: Signaling networks downstream of receptor tyrosine kinases are among the most extensively studied biological networks, but new approaches are needed to elucidate causal relationships between network components and understand how such relationships are influenced by biological context and disease. Here, we investigate the context specificity of signaling networks within a causal conceptual framework using reverse-phase protein array time-course assays and network analysis approaches. We focus on a well-defined set of signaling proteins profiled under inhibition with five kinase inhibitors in 32 contexts: four breast cancer cell lines (MCF7, UACC812, BT20, and BT549) under eight stimulus conditions. The data, spanning multiple pathways and comprising ∼70,000 phosphoprotein and ∼260,000 protein measurements, provide a wealth of testable, context-specific hypotheses, several of which we experimentally validate. Furthermore, the data provide a unique resource for computational methods development, permitting empirical assessment of causal network learning in a complex, mammalian setting.
authors.affiliation: MRC Biostatistics Unit, University of Cambridge, Cambridge CB2 0SR, UK.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hill
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97201, USA.
authors.forename: Nicole K
authors.initials: NK
authors.lastname: Nesser
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97201, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Johnson-Camacho
authors.affiliation: Kantar Health, Foster City, CA 94404, USA.
authors.forename: Mara
authors.initials: M
authors.lastname: Jeffress
authors.affiliation: Bayer Healthcare North America, Berkeley, CA 94710, USA.
authors.forename: Aimee
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97201, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Boniface
authors.affiliation: Department of Statistics, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Simon E F
authors.initials: SE
authors.lastname: Spencer
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97201, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Heiser
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97201, USA.
authors.forename: Yancey
authors.initials: Y
authors.lastname: Lawrence
authors.affiliation: Department of Obstetrics and Gynecology, Women's Health Research Unit, Oregon Health and Science University, Portland, OR 97239, USA; Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Nupur T
authors.initials: NT
authors.lastname: Pande
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97201, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Korkola
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR 97201, USA; Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA; Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: MRC Biostatistics Unit, University of Cambridge, Cambridge CB2 0SR, UK; German Center for Neurodegenerative Diseases (DZNE), Bonn 53127, Germany. Electronic address: sach.mukherjee@dzne.de.
authors.forename: Sach
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97201, USA. Electronic address: spellmap@ohsu.edu.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Spellman
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D010750:Phosphoproteins / Q000032:analysis*; D010766:Phosphorylation; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000502:physiology
chemical_list: D010750:Phosphoproteins
keywords: breast cancer cell lines; casual networks; computational systems biology; context-specific networks; data resource; empirical assessment; network inference; protein signaling networks; reverse-phase protein array data