Relaxation oscillations and hierarchy of feedbacks in MAPK signaling

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http://hdl.handle.net/10138/174083

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Kochanczyk , M , Kocieniewski , P , Kozlowska , E , Jaruszewicz-Blonska , J , Sparta , B , Pargett , M , Albeck , J G , Hlavacek , W S & Lipniacki , T 2017 , ' Relaxation oscillations and hierarchy of feedbacks in MAPK signaling ' , Scientific Reports , vol. 7 , 38244 . https://doi.org/10.1038/srep38244

Title: Relaxation oscillations and hierarchy of feedbacks in MAPK signaling
Author: Kochanczyk, Marek; Kocieniewski, Pawel; Kozlowska, Emilia; Jaruszewicz-Blonska, Joanna; Sparta, Breanne; Pargett, Michael; Albeck, John G.; Hlavacek, William S.; Lipniacki, Tomasz
Contributor: University of Helsinki, Research Programs Unit
Date: 2017-01-03
Language: eng
Number of pages: 15
Belongs to series: Scientific Reports
ISSN: 2045-2322
URI: http://hdl.handle.net/10138/174083
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.
Subject: PROTEIN-KINASE CASCADES
NEGATIVE-FEEDBACK
CELL FATE
RAS ACTIVATION
EGF-RECEPTOR
ERK
MECHANISMS
NETWORKS
PATHWAY
PROLIFERATION
3111 Biomedicine
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