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. Author manuscript; available in PMC: 2025 Jul 23.
Published in final edited form as: Physiol Rev. 2025 Jan 15;105(3):1291–1428. doi: 10.1152/physrev.00034.2023

Figure 10. c-Met/NOX4 axis contributes to metastasis and drug resistance in BRAF mutated melanoma.

Figure 10.

Proposed role of the c-MET axis and NOX4 in melanoma resistance and progression. Putative NOX4-mediated oxidation of BRAF at CR1 heightens NRAS leads to epithelial to mesenchymal transition and resistance to BRAF inhibitors in BRAF-mutated melanoma. BRAF proteins have 3 conserved (CR1, CR2, CR3), CR1 contains Ras binding domain where NRAS can bind, and a cysteine-rich subdomain that can be oxidized by NOX4-derived H2O2 leading to exaggerated resistance to BRAF inhibitors and melanoma progression. CR, Conserved region; RBD, Ras binding domain; CRB, cysteine-rich subdomain; AS, activation segment; NRAS: neuroblastoma Ras viral oncogene homolog.