The Ras-MAPK signaling pathway and associated mutations. (A) Schematic of the Ras-MAPK signaling pathway. Proteins commonly mutated in RASopathies, color coded to represent different syndromes: Noonan syndrome (NS; blue), cardio-facio-cutaneous syndrome (CFC; green), neurofibromatosis type 1 (NF1; magenta), Costello syndrome (CS; red), Legius syndrome (LS; purple). (B) Positions of mutations in certain genes that encode components of the Ras-MAPK pathway. Purple arrows indicate where a mutation has been modeled in animals; red arrows indicate where it has not. Colored boxes represent regions in the genes that encode key protein domains. In the RAS proteins, the G regions (blue) form the nucleotide-binding site, and the switch regions (green) change conformation between the inactive and active states. In the RAF proteins, the CR1 region (red) contains a Ras-binding domain, the CR2 (gray) and CR3 (turquoise) regions associate with 14-3-3 proteins (a family of key regulatory proteins expressed in all eukaryotic cells). The CR2 region is also a site of regulatory phosphorylation. In the SHP2 protein, structural features include the N (brown) and C (purple) terminal Src homology 2 (SH2) domains, and a protein tyrosine phosphate (PTP) domain (pink). In the MEK protein, key protein domains include the negative regulatory region (NRR; black), the MAPK-binding site (ERK binding; orange), the nuclear export signal (NES; green) and the catalytic core (yellow). Numbers near the arrows indicate the protein residues that are mutated (see supplementary material Table S1 for more details). RTK, receptor tyrosine kinase.