SHOC2-MRAS-PP1C complex (SHOC2-MRAS-PP1C)

The SHOC2-MRAS-PP1C complex is a critical ternary protein assembly that functions as a specific phosphatase for the RAF family of kinases. It is composed of the leucine-rich repeat scaffold protein SHOC2, the small GTPase MRAS, and the catalytic subunit of protein phosphatase 1 (PP1C). This complex is responsible for dephosphorylating the inhibitory '14-3-3 binding site' (S259 in C-RAF) on RAF proteins, a prerequisite step for RAF translocation to the plasma membrane and its subsequent activation by RAS. By facilitating the transition of RAF from an inactive to an active state, the complex serves as a vital node in the MAPK/ERK signaling cascade. Dysregulation of the SHOC2-MRAS-PP1C complex is heavily implicated in oncogenesis and developmental disorders. Germline mutations in SHOC2 or MRAS cause Noonan-like syndrome, while the complex is frequently exploited by RAS-mutant cancers to maintain high levels of ERK signaling and develop resistance to MEK or BRAF inhibitors. Consequently, the complex has emerged as a high-value therapeutic target. Current drug discovery efforts, such as those by Revolution Medicines, focus on developing 'molecular glue' or small-molecule inhibitors that disrupt the formation of this ternary complex to effectively shut down the MAPK pathway in RAS-driven tumors.

Other names

SHOC2-MRAS-PP1 phosphatase complexSur-8-MRAS-PP1C complexRAF S259 phosphatase complexSHOC2-MRAS-PP1CA complex

Inhibition of the ternary complex assembly or activity to prevent the dephosphorylation of the inhibitory S259 site on RAF kinases, thereby blocking RAF activation and downstream MAPK signaling.