M-Ras distinct activation scenarios: A mechanistic outlook and targeting.

ABSTRACT: The conformational states of canonical Ras (H-, K-, and N-Ras) GTPases define their nucleotide-exchange and effector binding capabilities. M-Ras, whose mutational variants can cause cancer directly, and indirectly through their complexes, appear to be one exception. Unlike canonical Ras, the GTP-bound M-Ras is mostly in the inactive state. The active state is stabilized in the holophosphatase ternary complex, which includes SHOC2 scaffolding protein and protein phosphatase-1 (PP1). PP1 dephosphorylates Raf's inhibitory site, promoting Raf activation and MAPK signaling and contributing to Noonan syndrome phenotype. Activating Q71R variant (M-Ras^Q71R) exhibits higher affinity than the wild type to holophosphatase. With allosteric drug discovery benefitting from insight into

SUBMITTER: Xu L 

PROVIDER: S-EPMC12670535 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature