Leucine-rich repeat protein SHOC-2–Muscle RAS oncogene homolog–Protein phosphatase 1 catalytic subunit holophosphatase complex (SMP complex) (SMP complex)

The SHOC2-MRAS-PP1C (SMP) holophosphatase complex is a heterotrimeric protein assembly that acts as a key regulator of the RAS-MAPK signaling pathway [1, 13]. It is composed of the leucine-rich repeat (LRR) scaffolding protein SHOC2, the small GTPase MRAS, and the catalytic subunit of protein phosphatase 1 (PP1C) [2, 11]. The complex's primary biological function is to dephosphorylate the inhibitory conserved region 2 (CR2) phosphoserine site on RAF kinases (e.g., S259 in CRAF, S365 in BRAF), a step essential for releasing RAF from its autoinhibited state and allowing it to dimerize and activate the downstream MAPK cascade [5, 15]. Mutations in the components of the SMP complex are associated with RASopathies, such as Noonan syndrome, and the complex is a major driver of resistance to MEK inhibitors in RAS-mutant cancers [11, 17]. Consequently, the SMP complex has emerged as a high-priority therapeutic target, with drug discovery efforts focusing on small-molecule inhibitors and degraders that disrupt its assembly to block oncogenic signaling [8, 16].

Other names

SHOC2-MRAS-PP1C ternary complexSHOC2-MRAS-PP1C complexMRAS-SHOC2-PP1C complexSHOC2-MRAS-PP1C holophosphataseSMP complex

Inhibition of the SHOC2-MRAS-PP1C complex assembly or protein degradation to prevent the dephosphorylation of RAF kinases, thereby blocking the reactivation of the MAPK signaling pathway [8, 13].