Seminarium z cyklu Mathematical Modelling in Biology and Medicine (8 maja 2017)
Podczas kolejnego seminarium z cyklu Mathematical Modelling in Biology and Medicine Marek Kochańczyk z Instytutu Podstawowych Problemów Techniki PAN wygłosi referat pt. MAPK signaling I: Focus on feedbacks.
Serdecznie zapraszamy!
Abstrakt wystąpienia:
Pathways responsible for sensing extracellular ligands, such as the mitogen-activated protein kinase (MAPK) cascades, do not simply transduce information but process it by means of temporally ordered modifications of cascade components, which may be involved in negative and positive feedback loops. By mathematical modeling of a canonical MAPK cascade, namely the RAF–MEK–ERK cascade, we characterized the relation between topology of intertwined feedback loops and ERK activation dynamics, and proposed a sequence of plausible post-translational modifications of RAF.
In the first part of the seminar we will demonstrate how two feedbacks – a negative feedback loop involving ERK and SOS and a positive feedback coupling RAS and SOS, which is embedded in that negative feedback loop – are sufficient to generate oscillations that resemble pulsatile ERK responses of epidermal growth factor (EGF) dose-dependent frequencies, observed by John Albeck and colleagues using KTR and FRET sensors in single cells at low-dose EGF stimulations. Two other negative feedback loops emanating from ERK to RAF and to MEK, which lie downstream the positive feedback loop, appear to only modulate the shape of pulses. 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 likely allows the MAPK cascade to convert paracrine EGF signals into spatially non-uniform ERK activity pulses.