Leucine-rich repeat protein SHOC-2 (SHOC2)

Leucine-rich repeat protein SHOC-2 is a highly conserved scaffold protein consisting primarily of leucine-rich repeats (LRRs) that form a horseshoe-shaped structure for protein-protein interactions. It serves as a core component of the SHOC2-MRAS-PP1c (SMP) complex, which dephosphorylates inhibitory sites on RAF kinases (Ser-259 on RAF1, Ser-365 on BRAF, Ser-214 on ARAF), thereby activating the RAF-MEK-ERK MAPK signaling cascade downstream of RAS. This scaffolding enhances signal specificity, amplitude, and spatial control, including endosomal targeting, while interacting with regulators like HUWE1 (for ubiquitination) and PSMC5 (for complex remodeling). SHOC-2 is essential for embryogenesis, as its knockout causes lethality in mice due to heart defects, and it promotes cell proliferation and self-renewal in neuronal progenitors. Gain-of-function mutations, such as S2G, cause Noonan-like syndrome with loose anagen hair by hyperactivating ERK signaling via aberrant membrane targeting. In cancer, SHOC-2 sustains ERK activity in tumors with RAS or RAF mutations, contributing to resistance against BRAF inhibitors like vemurafenib and promoting motility and anchorage-independent growth. No approved drugs directly target SHOC-2, but its central role in RASopathy signaling positions it as a potential therapeutic target, though challenges include avoiding developmental toxicity.

Other names

Leucine rich repeat scaffold proteinSur-8SHOC-2