title: Relaxation oscillations and hierarchy of feedbacks in MAPK signaling.
abstract: We formulated a computational model for a MAPK signaling cascade downstream of the EGF receptor to investigate how interlinked positive and negative feedback loops process EGF signals into ERK pulses of constant amplitude but dose-dependent duration and frequency. A positive feedback loop involving RAS and SOS, which leads to bistability and allows for switch-like responses to inputs, is nested within a negative feedback loop that encompasses RAS and RAF, MEK, and ERK that inhibits SOS via phosphorylation. This negative feedback, operating on a longer time scale, changes switch-like behavior into oscillations having a period of 1 hour or longer. Two auxiliary negative feedback loops, from ERK to MEK and RAF, placed downstream of the positive feedback, shape the temporal ERK activity profile but are dispensable for oscillations. Thus, the positive feedback introduces a hierarchy among negative feedback loops, such that the effect of a negative feedback depends on its position with respect to the positive feedback loop. Furthermore, a combination of the fast positive feedback involving slow-diffusing membrane components with slower negative feedbacks involving faster diffusing cytoplasmic components leads to local excitation/global inhibition dynamics, which allows the MAPK cascade to transmit paracrine EGF signals into spatially non-uniform ERK activity pulses.
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Kochańczyk
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Kocieniewski
authors.affiliation: Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Kozłowska
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jaruszewicz-Błońska
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, California, United States of America.
authors.forename: Breanne
authors.initials: B
authors.lastname: Sparta
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Pargett
authors.affiliation: Department of Molecular and Cellular Biology, University of California, Davis, California, United States of America.
authors.forename: John G
authors.initials: JG
authors.lastname: Albeck
authors.affiliation: Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: William S
authors.initials: WS
authors.lastname: Hlavacek
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lipniacki
mesh_terms: D003198:Computer Simulation; D066246:ErbB Receptors / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins