Regulation of the MAPK/ERK system: a computational rule-based model

MAPK/ERK pathway coordinates multiple cellular functions, including proliferation, apoptosis, and motility, yet it is frequently modeled as a one-purpose cascade. Pathway complexity is a consequence of the existence of isoforms of pathway components that are regulated differently and have specific interacting partners. Here, we propose a rule-based model of the MAPK/ERK pathway that accounts for differential regulation of MEK and RAF isoforms and RAF interactions with 14-3-3 proteins. The model addressed signaling based on the enzymatic cascade as well as regulatory protein-protein interactions. We propose that at low concentrations of growth factors, RAS is activated only in a portion of the membrane. This allows the model to reconcile the observed switch-like and graded responses observed at upper and lower tiers of the pathway, respectively. We demonstrate that functional differences between BRAF and CRAF or ARAF can follow from their different interaction with 14-3-3. The 14-3-3 dimers inhibit all RAF isoforms in close form, but preferentially stabilize BRAF-CRAF dimers to BRAF-BRAF homodimers, and may not stabilize RAF dimers without BRAF. The constructed model allows for the exploration of qualitative differences in MAPK/ERK pathway signaling observed in different cell lines.