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. 2023 Jul 14;9(28):eadf4766. doi: 10.1126/sciadv.adf4766

Fig. 10. Model of MAPK pathway activation by mutant RIT1.

Fig. 10.

Cancer and NS-associated pathogenic RIT1 variants promote MAPK pathway activation in a classical RAS-dependent manner. Mutant RIT1 proteins evade LZTR1-mediated proteasomal degradation and accumulate at the PM residing in close proximity to RAS. Pathogenic RIT1 accumulation drives RAF recruitment to the PM via the RAF-RBD but inefficient CRD engagement limits RAF activation. However, the increased local concentration of RAF promotes its activation by RAS molecules in response to upstream RTK signaling. Inhibition of various RTK-RAS-MAPK signaling components (e.g., SHP2, SOS1, RAF, and MEK) abated aberrant MAPK activation by mutant RIT1. KD, kinase domain.