Relaxation oscillations and hierarchy of feedbacks in MAPK signaling

Marek Kochańczyk, Paweł Kocieniewski, Emilia Kozłowska, Joanna Jaruszewicz-Błońska, Breanne Sparta, Michael Pargett, John Albeck, William S. Hlavacek, Tomasz Lipniacki

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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.

Original languageEnglish (US)
Article number38244
JournalScientific Reports
Volume7
DOIs
StatePublished - Jan 3 2017

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Mitogen-Activated Protein Kinase Kinases
Epidermal Growth Factor
Epidermal Growth Factor Receptor
Phosphorylation
Membranes

ASJC Scopus subject areas

  • General

Cite this

Kochańczyk, M., Kocieniewski, P., Kozłowska, E., Jaruszewicz-Błońska, J., Sparta, B., Pargett, M., ... Lipniacki, T. (2017). Relaxation oscillations and hierarchy of feedbacks in MAPK signaling. Scientific Reports, 7, [38244]. https://doi.org/10.1038/srep38244

Relaxation oscillations and hierarchy of feedbacks in MAPK signaling. / Kochańczyk, Marek; Kocieniewski, Paweł; Kozłowska, Emilia; Jaruszewicz-Błońska, Joanna; Sparta, Breanne; Pargett, Michael; Albeck, John; Hlavacek, William S.; Lipniacki, Tomasz.

In: Scientific Reports, Vol. 7, 38244, 03.01.2017.

Research output: Contribution to journalArticle

Kochańczyk, M, Kocieniewski, P, Kozłowska, E, Jaruszewicz-Błońska, J, Sparta, B, Pargett, M, Albeck, J, Hlavacek, WS & Lipniacki, T 2017, 'Relaxation oscillations and hierarchy of feedbacks in MAPK signaling', Scientific Reports, vol. 7, 38244. https://doi.org/10.1038/srep38244
Kochańczyk M, Kocieniewski P, Kozłowska E, Jaruszewicz-Błońska J, Sparta B, Pargett M et al. Relaxation oscillations and hierarchy of feedbacks in MAPK signaling. Scientific Reports. 2017 Jan 3;7. 38244. https://doi.org/10.1038/srep38244
Kochańczyk, Marek ; Kocieniewski, Paweł ; Kozłowska, Emilia ; Jaruszewicz-Błońska, Joanna ; Sparta, Breanne ; Pargett, Michael ; Albeck, John ; Hlavacek, William S. ; Lipniacki, Tomasz. / Relaxation oscillations and hierarchy of feedbacks in MAPK signaling. In: Scientific Reports. 2017 ; Vol. 7.
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