title: Dissecting the interface between signaling and transcriptional regulation in human B cells.
abstract: A key role of signal transduction pathways is to control transcriptional programs in the nucleus as a function of signals received by the cell via complex post-translational modification cascades. This determines cell-context specific responses to environmental stimuli. Given the difficulty of quantitating protein concentration and post-translational modifications, signaling pathway studies are still for the most part conducted one interaction at the time. Thus, genome-wide, cell-context specific dissection of signaling pathways is still an open challenge in molecular systems biology. In this manuscript we extend the MINDy algorithm for the identification of posttranslational modulators of transcription factor activity, to produce a first genome-wide map of the interface between signaling and transcriptional regulatory programs in human B cells. We show that the serine-threonine kinase STK38 emerges as the most pleiotropic signaling protein in this cellular context and we biochemically validate this finding by shRNA-mediated silencing of this kinase, followed by gene expression profile analysis. We also extensively validate the inferred interactions using protein-protein interaction databases and the kinase-substrate interaction prediction algorithm NetworKIN.
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, NY, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Mariano J
authors.initials: MJ
authors.lastname: Alvarez
authors.forename: Brygida C
authors.initials: BC
authors.lastname: Bisikirska
authors.forename: Rune
authors.initials: R
authors.lastname: Linding
authors.forename: Katia
authors.initials: K
authors.lastname: Basso
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla Favera
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
mesh_terms: D000465:Algorithms; D001402:B-Lymphocytes / Q000378:metabolism*; D001699:Biometry; D002460:Cell Line; D016208:Databases, Factual; D030541:Databases, Genetic; D020869:Gene Expression Profiling / Q000706:statistics & numerical data; D053263:Gene Regulatory Networks; D006801:Humans; D008954:Models, Biological; D025941:Protein Interaction Mapping / Q000706:statistics & numerical data; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D021382:Protein Sorting Signals; D014157:Transcription Factors