Seminarium z cyklu Mathematical Modelling in Biology and Medicine (22 maja 2017)
Podczas kolejnego seminarium z cyklu Mathematical Modelling in Biology and Medicine Paweł Kocieniewski z Instytutu Podstawowych Problemów Techniki PAN wygłosi referat pt. MAPK signaling II: Focus on RAF-1 interactions.
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 second part of the seminar we will focus on RAF activation dynamics analyzed by means of a rule-based model developed and parametrized based on a large array of Western blot data from the Manuela Baccarini group. The model accounts for differences between two main RAF isoforms, BRAF and RAF-1, and implements regulatory mechanisms that recapitulate dynamics of specific phosphorylated forms of BRAF and RAF-1. We show that RAF1 in addition to a phoshorylated form capable of relaying signal to MEK assumes also an alternative phosphorylated form that can inhibit the kinase ROKα, a regulator of cytoskeletal rearrangements. This may explain how coordination of the timing of proliferation with changes in cell shape, adhesion, or motility can be achieved within the MAPK cascade.