title: Sorad: a systems biology approach to predict and modulate dynamic signaling pathway response from phosphoproteome time-course measurements.
abstract: BACKGROUND
  Signaling networks mediate responses to different stimuli using a multitude of feed-forward, feedback and cross-talk mechanisms, and malfunctions in these mechanisms have an important role in various diseases. To understand a disease and to help discover novel therapeutic approaches, we have to reveal the molecular mechanisms underlying signal transduction and use that information to design targeted perturbations.
  
  
  RESULTS
  We have pursued this direction by developing an efficient computational approach, Sorad, which can estimate the structure of signal transduction networks and the associated continuous signaling dynamics from phosphoprotein time-course measurements. Further, Sorad can identify experimental conditions that modulate the signaling toward a desired response. We have analyzed comprehensive phosphoprotein time-course data from a human hepatocellular liver carcinoma cell line and demonstrate here that Sorad provides more accurate predictions of phosphoprotein responses to given stimuli than previously presented methods and, importantly, that Sorad can estimate experimental conditions to achieve a desired signaling response. Because Sorad is data driven, it has a high potential to generate novel hypotheses for further research. Our analysis of the hepatocellular liver carcinoma data predict a regulatory connection where AKT activity is dependent on IKK in TGFα stimulated cells, which is supported by the original data but not included in the original model.
  
  
  BACKGROUND
  An implementation of the proposed computational methods will be available at http://research.ics.aalto.fi/csb/software/.
  
  
  BACKGROUND
  tarmo.aijo@aalto.fi or harri.lahdesmaki@aalto.fi
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Information and Computer Science, Aalto University, FI-00076 AALTO, Finland. tarmo.aijo@aalto.fi
authors.forename: Tarmo
authors.initials: T
authors.lastname: Äijö
authors.forename: Kirsi
authors.initials: K
authors.lastname: Granberg
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D010750:Phosphoproteins / Q000032:analysis* / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D012984:Software; D049490:Systems Biology / Q000379:methods*
chemical_list: D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt