Fig. 7
From: Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation
Model of the impact of phosphorylation on KRAS GTPase cycle and structural rationale. a Phosphorylation decouples KRAS from effectors and GTPase cycle regulation. The GTPase cycle of unmodified KRAS is shown on top. Nucleotide exchange and hydrolysis are accelerated by the activities of GEFs and GAPs, respectively. GTP-loaded KRAS binds and activates RAF. Src phosphorylation of Tyr32 and Tyr64 of KRAS-GDP or KRAS-GTP alters all steps in this GTPase cycle (lower part). Upon phosphorylation, KRAS becomes insensitive to regulation by both GEFs and GAPs, whereas intrinsic nucleotide exchange is enhanced and intrinsic GTP hydrolysis is impaired. This leads to the accumulation of phosphorylated KRAS-GTP, which has reduced affinity for RAF, thus phosphorylation limits KRAS signaling. SHP2 dephosphorylates KRAS and thereby unleashes KRAS-GTP to rapidly activate RAF. Inhibition of SHP2 promotes accumulation of phosphorylated KRAS, dampening RAF signaling and subsequently suppressing oncogenesis. Line thickness and number of arrowheads represent relative reaction rates of each step. b Ribbon diagram SOS (green) contact with Tyr32 and Tyr64 of RAS (PDB ID 1BKD). c Proposed coordination of switch I and switch II RAS residues in intrinsic GTP hydrolysis (PDB ID 4G0N). d Switch I and II (blue) of RAS are the main interaction site with GAP (green) (PDB ID 1WQ1)
