Feedback control in the MAPK signaling module Pubmed17310240 Reactome Database ID Release 43197529 Reactome, http://www.reactome.org ReactomeREACT_22434 The RAF/MEK/ERK network topology underlies ERK dynamics, which is believed to be a major cause of the diversity in cellular response to stimulation of different growth factor receptors. Topological differences exist in such networks, dependent on whether cells are activated with EGF or NGF. On EGF stimulation, the network exhibits negative feedback only whereas a positive feedback is apparent on NGF stimulation. The latter confers stability to ERK activation, thereby governing differentiation (in PC12 cells) upon stimulation with NGF, but not EGF (Santos S.D. et al, 2007). The negative feedback observed on EGF stimulation controls the transient activation of ERK1/2, and is mediated by ERK1/2 down regulation of SOS. The positive feedback observed on NGF stimulation involves PKC, mainly PKC-delta, which acts upstream of the MAPK module, the RAF kinase inhibitory protein RKIP, and ERK, which phosphorylates RAF, increasing its activity.