title: Regulation of ras signaling dynamics by Sos-mediated positive feedback.
abstract: The RTK-Ras-ERK cascade is a central signaling module implicated in the control of diverse biological processes including cell proliferation, differentiation, and survival. The coupling of RTK to Ras is mediated by the Ras-specific nucleotide-exchange factor Son of Sevenless (Sos), which activates Ras by inducing the exchange of GDP for GTP . Considerable evidence indicates that the duration and amplitude of Ras signals are important determinants in controlling the biological outcome . However, the mechanisms that regulate the quantitative output of Ras signaling remain poorly understood. We define a previously unrecognized regulatory component of the machinery that specifies the kinetic properties of signals propagated through the RTK-Ras-ERK cascade. We demonstrate that the establishment of a positive feedback loop involving Ras.GTP and Sos leads to an increase in the amplitude and duration of Ras activation in response to EGF stimulation. This effect is propagated to downstream elements of the pathway as reflected by sustained EGF-induced ERK phosphorylation and enhanced SRE-dependent transcription. As a consequence, the physiological endpoint of EGF action is switched from proliferation to differentiation. We propose that the engagement of Ras/Sos positive feedback loop may contribute to the mechanism by which ligand stimulation is coupled to discrete biological responses.
authors.affiliation: Department of Molecular Genetics and Microbiology, State University of New York, at Stony Brook, Stony Brook, New York 11794, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Boykevisch
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Holger
authors.initials: H
authors.lastname: Sondermann
authors.forename: Polyxeni
authors.initials: P
authors.lastname: Philippidou
authors.forename: Simon
authors.initials: S
authors.lastname: Halegoua
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological; D006367:HeLa Cells; D006801:Humans; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D020664:Son of Sevenless Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D020664:Son of Sevenless Proteins; D020794:Receptor Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins