RAS Family Interactions: The SHOC2-MRAS-PP1 Complex in Noonan Syndrome

SHOC2, a scaffold-type protein, MRAS, a close relative of the RAS oncoproteins, and protein phosphatase 1 (PP1) form a complex (SHOC2-MRAS-PP1 or SMP complex) that dephosphorylates the “259” inhibitory site in RAF kinases and promotes RAF dimerization and downstream signaling. This regulatory node in RAF activation selectively contributes to the ERK-MAPK pathway, being critical in the context of oncogenic RAS but dispensable in other contexts, making it an attractive therapeutic target for inhibition of RAS-driven cancers. Gain-of-function germline mutations in SHOC2 and PP1 are responsible for the RASopathy Noonan-like syndrome with Loose Anagen Hair (NSLH), whereas activating MRAS mutations are found in a few cases of Noonan syndrome with cardiomyopathy. Recent structural insights into the SMP complex and biochemical characterization of syndromic mutations reveal how they promote complex formation and highlight a key role for RAF “S259” dephosphorylation in Noonan syndrome pathogenesis. Thus, novel therapeutic strategies targeting SHOC2 and/or the SMP complex should be studied in the context of both RAS-driven cancers and RASopathies.