Modelling oncogenic Ras/Raf signalling in the mouse

Abstract

The Ras/Raf/MEK/ERK (or MAPK) signalling pathway relays extracellular stimuli to the nucleus, thereby regulating diverse cellular responses such as proliferation, growth, differentiation and apoptosis. Perturbation of these processes by aberrant MAPK signalling often leads to malignant transformation as indicated by the frequent occurrence in human cancers of genetic alterations affecting this pathway. In recent years, genetically modified mouse models have proven instrumental in unravelling how deregulated MAPK signalling leads to disease. Indeed, conditional activation of oncogenic K-Ras or B-Raf in mice resulted in neoplasms that closely resemble the human disease. Such tractable mouse models will enable the pursuit of basic biological mechanisms and translational applications regarding the MAPK pathway.

Figure 1

The Ras/Raf/MEK/ERK pathway. Binding of growth factors (GF) to receptor tyrosine kinases (RTK) leads to recruitment of adaptor proteins and guanine exchange factors (GEF). GEFs promote the active form of Ras (RasGTP). Ras signals to different pathways, one being the Raf/MEK/ERK pathway. Ras activates Raf, which may have several downstream effectors. Raf phosphorylates MEK followed by ERK phosphorylated by MEK. ERK has cytoplasmic substrates and also translocates to the nucleus to activate a variety of transcriptional programmes through several transcription factors (TFs). The signalling cascade is negatively regulated by Sprouty proteins (SPRY) and dual-specificity phosphatases (DUSP). Proteins in red have been found genetically altered in human cancers resulting in hyperactivation of the MAPK pathway.