Tian-Rui Xu, Vladislav Vyshemirsky, Amélie Gormand, Alex von Kriegsheim, Mark Girolami, George S Baillie, Dominic Ketley, Allan J Dunlop, Graeme Milligan, Miles D Houslay, Walter Kolch
{"title":"Inferring signaling pathway topologies from multiple perturbation measurements of specific biochemical species.","authors":"Tian-Rui Xu, Vladislav Vyshemirsky, Amélie Gormand, Alex von Kriegsheim, Mark Girolami, George S Baillie, Dominic Ketley, Allan J Dunlop, Graeme Milligan, Miles D Houslay, Walter Kolch","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The specification of biological decisions by signaling pathways is encoded by the interplay between activation dynamics and network topologies. Although we can describe complex networks, we cannot easily determine which topology the cell actually uses to transduce a specific signal. Experimental testing of all plausible topologies is infeasible because of the combinatorially large number of experiments required to explore the complete hypothesis space. Here, we demonstrate that Bayesian inference-based modeling provides an approach to explore and constrain this hypothesis space,permitting the rational ranking of pathway models. Our approach can use measurements of a limited number of biochemical species when combined with multiple perturbations. As proof of concept, we examined the activation of the extracellular signal-regulated kinase (ERK) pathway by epidermal growth factor. The predicted and experimentally validated model shows that both Raf-1 and, unexpectedly,B-Raf are needed to fully activate ERK in two different cell lines. Thus, our formal methodology rationally infers evidentially supported pathway topologies even when a limited number of biochemical and kinetic measurements are available.</p>","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"3 134","pages":"ra20"},"PeriodicalIF":7.3,"publicationDate":"2010-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29205816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Making Memories Last","authors":"P. Stern","doi":"10.1126/science.325_919e","DOIUrl":"https://doi.org/10.1126/science.325_919e","url":null,"abstract":"Pharmacological and biochemical analyses reveal that dopamine determines the duration of fear memory storage. How can memory traces persist over days or weeks, despite the short-lived nature and rapid turnover of their molecular substrates? It has recently been reported that, in order to persist, an otherwise rapidly forgotten long-term memory requires BDNF (brain-derived neurotrophic factor) expression in the hippocampus 12 hours after training. Rossato et al. now show that this mechanism is gated into action by activation of the ventral tegmental area acting upon dopamine D1 receptors in the hippocampus. Time-limited N-methyl-D-aspartate receptor–dependent activity in the ventral tegmental area–hippocampal circuitry underlies the delayed increase in BDNF levels in the hippocampus 12 hours after inhibitory avoidance, a hippocampus-dependent form of learning. J. I. Rossato, L. R. M. Bevilaqua, I. Izquierdo, J. H. Medina, M. Cammarota, Dopamine controls persistence of long-term memory storage. Science 325, 1017–1020 (2009). [Abstract] [Full Text]","PeriodicalId":49560,"journal":{"name":"Science Signaling","volume":"37 1","pages":"ec285 - ec285"},"PeriodicalIF":7.3,"publicationDate":"2009-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89174011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}