{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSHOC2 is a highly conserved, leucine‐rich repeat scaffold protein that plays a pivotal role in modulating RAS–MAPK/ERK pathway activation. It facilitates signal propagation by promoting the dynamic association between key components of this cascade – notably by bridging activated RAS with RAF kinases and by assembling complexes with MRAS and the protein phosphatase PP1. Through this scaffolding function, SHOC2 accelerates both the association and dissociation kinetics of the Ras–Raf interaction and catalyzes the dephosphorylation of RAF at the inhibitory S259 residue, thereby licensing RAF activation and fine‐tuning spatio‐temporal ERK signaling responses, including those driven by calcium and other secondary messengers. This mechanistic role has been elucidated by studies demonstrating that aberrant lipid modification (N‑myristoylation) or loss of adequate cytosolic shuttling of SHOC2 markedly alters its localization and enhances MAPK pathway output."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in SHOC2 have emerged as a key cause of several RASopathy syndromes, most notably Noonan‐like syndrome with loose anagen hair. A recurrent p.Ser2Gly mutation creates an aberrant myristoylation motif that misdirects SHOC2 to the plasma membrane and disrupts its normal nucleocytoplasmic shuttling, leading to sustained and dysregulated ERK activity. Such gain‐of‐function changes, along with other pathogenic variants, contribute to a spectrum of developmental and cardiac defects, occasionally accompanied by immunological or autoimmune features. Clinical studies and molecular analyses have thus linked the proper regulation of SHOC2 function to both normal development and the pathogenesis of these congenital disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond developmental disorders, SHOC2 has been implicated in oncogenesis and cancer drug resistance. In various malignancies—including thyroid, breast, and colorectal cancers—SHOC2 underpins oncogenic RAS–MAPK signaling and has been shown to mediate cellular processes such as proliferation, migration, and anchorage-independent growth. Its role as an essential facilitator of RAF activation renders cancer cells particularly dependent on SHOC2 for survival, suggesting that attenuation of its function can synergize with MEK inhibitors and other targeted agents. Recent structural studies, including high‑resolution cryo–electron microscopy and the development of synthetic single‐domain antibodies, have provided further insights into the composition of the SHOC2–MRAS–PP1 holoenzyme, thereby identifying novel opportunities for therapeutic intervention in RAS‐driven tumors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Viviana Cordeddu, Elia Di Schiavi, Len A Pennacchio, et al. 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