title: Receptor Level Mechanisms Are Required for Epidermal Growth Factor (EGF)-stimulated Extracellular Signal-regulated Kinase (ERK) Activity Pulses.
abstract: In both physiological and cell culture systems, EGF-stimulated ERK activity occurs in discrete pulses within individual cells. Many feedback loops are present in the EGF receptor (EGFR)-ERK network, but the mechanisms driving pulsatile ERK kinetics are unknown. Here, we find that in cells that respond to EGF with frequency-modulated pulsatile ERK activity, stimulation through a heterologous TrkA receptor system results in non-pulsatile, amplitude-modulated activation of ERK. We further dissect the kinetics of pulse activity using a combination of FRET- and translocation-based reporters and find that EGFR activity is required to maintain ERK activity throughout the 10-20-minute lifetime of pulses. Together, these data indicate that feedbacks operating within the core Ras-Raf-MEK-ERK cascade are insufficient to drive discrete pulses of ERK activity and instead implicate mechanisms acting at the level of EGFR.
authors: From the Departments of Molecular and Cellular Biology and.
authors: Breanne
authors: B
authors: Sparta
authors: From the Departments of Molecular and Cellular Biology and.
authors: Michael
authors: M
authors: Pargett
authors: From the Departments of Molecular and Cellular Biology and.
authors: Marta
authors: M
authors: Minguet
authors: From the Departments of Molecular and Cellular Biology and.
authors: Kevin
authors: K
authors: Distor
authors: Microbiology and Molecular Genetics, University of California, Davis, California 95616.
authors: George
authors: G
authors: Bell
authors: From the Departments of Molecular and Cellular Biology and jgalbeck@ucdavis.edu.
authors: John G
authors: JG
authors: Albeck
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020917:Receptor, trkA / Q000378:metabolism
chemical_list: D004815:Epidermal Growth Factor; D020917:Receptor, trkA; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: EKAR; ERKTR; TRK1-transforming tyrosine kinase protein (Trk-A); epidermal growth factor receptor (EGFR); extracellular-signal-regulated kinase (ERK); fluorescence resonance energy transfer (FRET); mitogen-activated protein kinase (MAPK); nerve growth factor (NGF); signal transduction