title: Modulation of Rho GTPase signaling regulates a switch between adipogenesis and myogenesis.
abstract: Mature adipocytes and myocytes are derived from a common mesenchymal precursor. While IGF-1 promotes the differentiation of both cell types, the signaling pathways that specify the distinct cell fates are largely unknown. Here, we show that the Rho GTPase and its regulator, p190-B RhoGAP, are components of a critical switch in the adipogenesis-myogenesis "decision." Cells derived from embryos lacking p190-B RhoGAP exhibit excessive Rho activity, are defective for adipogenesis, but undergo myogenesis in response to IGF-1 exposure. In vitro, activation of Rho-kinase by Rho inhibits adipogenesis and is required for myogenesis. The activation state of Rho following IGF-1 signaling is determined by the tyrosine-phosphorylation status of p190-B RhoGAP and its resulting subcellular relocalization. Moreover, adjusting Rho activity is sufficient to alter the differentiation program of adipocyte and myocyte precursors. Together, these results identify the Rho GTPase as an essential modulator of IGF-1 signals that direct the adipogenesis-myogenesis cell fate decision.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sordella
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Guang-Chao
authors.initials: GC
authors.lastname: Chen
authors.forename: Marcello
authors.initials: M
authors.lastname: Curto
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000196:embryology* / Q000201:enzymology; D000818:Animals; D002451:Cell Compartmentation / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D008648:Mesoderm / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology* / Q000201:enzymology; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C513041:Arhgap35 protein, mouse; C513042:Arhgap5 protein, mouse; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D012097:Repressor Proteins; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D017526:Receptor, IGF Type 1; D020741:rho GTP-Binding Proteins