GNG2-MRAS interaction regulates SHOC2-dependent RAF activation and MAPK signaling

Full-length GNG2 and helical fragments (Δ1, Δ2) bind MRAS, disrupt SHOC2-MRAS-PP1C holophosphatase complex assembly, and thereby prevent RAF dephosphorylation.

• Why it matters: MAPK pathway dysregulation drives many cancers and RASopathies, and the SHOC2-MRAS-PP1C node is key for RAF activation, yet GNG2’s mechanism is unclear.
• What they did: Using NanoBiT live-cell bioluminescence, Co-IP, biolayer interferometry, and molecular dynamics, the study shows GNG2 variants (residues 1–71aa; Δ1 1–29aa; Δ2 30–71aa) target MRAS and block SMP formation.
• The result: Truncated GNG2 variants reduce ERK phosphorylation in cells, and a Δ2-derived peptide disrupts SMP complex formation in purified systems and live cells, attenuating MAPK signaling.

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