Fig. 2.

The RAS pathway. (A) Growth factor binding to RTKs, such as stem cell factor receptor (KIT), epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor (PDGFR), leads to receptor autophosphorylation and recruitment of the adaptor protein growth factor receptor bound 2 (GRB2). In turn, GRB2 recruits the guanine exchange factor SOS1/2, activating RAS. A main effector of the RAS pathway is the RAF/MEK/ERK (MAPK) cascade that leads to the transcription of different target genes (e.g. FOS, MYC, MDM2, MITF) implicated in cell proliferation, survival and cell cycle progression. The PI3K/AKT/mTOR (PI3K) pathway is another important effector of active RAS, promoting cell growth and implicated in melanoma development. Gray lines represent regulatory feedback loops. These include direct phosphorylation of SOS1/2 and RAFs by ERK, leading to dissociation of GRB2–SOS1/2 and RAS–RAF complexes, respectively, as well as the transcriptional induction of negative regulators, such as members of the DUSP, SPROUTY and SPRED families, i.e. DUSP4, DUSP5, DUSP6, SPRY1, SPRY2, SPRY3, SPRY4, SPRED1 and SPRED2. P, phosphate; SPRY, sprouty RTK signaling antagonists 1,2, 3 and 4. (B) Regulation of RAS activity by guanine nucleotide exchange factors (GEFs), such as SOS1 or 2, and GTPase-activating proteins (GAPs), such as NF1. GEFs stimulate the formation of the GTP-bound active state, whereas GAPs catalyze GTP hydrolysis and favor reverting to the GDP-bound inactive state.