title: Mapping growth-factor-modulated Akt signaling dynamics.
abstract: Growth factors alter cellular behavior through shared signaling cascades, raising the question of how specificity is achieved. Here, we have determined how growth factor actions are encoded into Akt signaling dynamics by real-time tracking of a fluorescent sensor. In individual cells, Akt activity was encoded in an analog pattern, with similar latencies (∼2 min) and half-maximal peak response times (range of 5-8 min). Yet, different growth factors promoted dose-dependent and heterogeneous changes in signaling dynamics. Insulin treatment caused sustained Akt activity, whereas EGF or PDGF-AA promoted transient signaling; PDGF-BB produced sustained responses at higher concentrations, but short-term effects at low doses, actions that were independent of the PDGF-α receptor. Transient responses to EGF were caused by negative feedback at the receptor level, as a second treatment yielded minimal responses, whereas parallel exposure to IGF-I caused full Akt activation. Small-molecule inhibitors reduced PDGF-BB signaling to transient responses, but only decreased the magnitude of IGF-I actions. Our observations reveal distinctions among growth factors that use shared components, and allow us to capture the consequences of receptor-specific regulatory mechanisms on Akt signaling.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Gross
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR 97239, USA Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech Health University Health Sciences Center, El Paso, TX 79905, USA peter.rotwein@ttuhsc.edu.
authors.forename: Peter
authors.identifier: 0000-0002-9505-1817
authors.initials: P
authors.lastname: Rotwein
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D007328:Insulin; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt
keywords: Akt; Live-cell imaging; Peptide growth factors; Signaling dynamics; Signaling pathways