fig2

Figure 2. Genetic mutations that hyperactivate the RAS/RAF/MEK/ERK signaling pathway in human cancers. The RAS/RAF/MEK/ERK signaling is initiated on the plasma membrane where engagement of EGFR by its ligand activates Sos. In turn, Sos functions as a RAS-GEF to catalyze the GTP loading on RAS. Subsequently, RAS-GTP triggers the RAF/MEK/ERK kinase cascade and ultimately activates ERK. As the terminal kinase of this signaling cascade, active ERK phosphorylates numerous substrates and induces diverse cell responses. This signaling cascade is tightly regulated under physiological conditions through complicated mechanisms that include MEK-mediated positive feedback (red arrows) as well as NF1-driven GTP hydrolysis and ERK-mediated negative feedback (blue arrows). In cancer cells, this signaling cascade is mainly hyperactivated by genetic mutations on EGFR, NF1, RAS, and RAF. The hotspots for oncogenic mutations in these genes are labeled as yellow stars. The mutational prevalence of these genes in different type of cancers (calculated from TCGA, cBio, and COSMIC databases) are shown in boxes. TCGA data are shown in small circles forming square, while COSMIC data and cBio data are shown as a donut plot and a box graph, respectively. Numbers on the legends indicate the percentages of mutations in the particular cancer types. EGF: Epidermal growth factor.