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Significance The physiological relevance of STAT2 (a member of STAT family) in melanoma formation is clearly shown using a human skin tissue array. Moreover, FBXW7-mediated STAT2 protein stability regulation via ubiquitination is shown to play an essential role in melanoma cell proliferation in monolayer and anchorage-independent 3D culture systems. The molecular mechanisms that regulate STAT2 protein stability by FBXW7 include the interaction between CCD and DBD domains of STAT2 and the WD40 domain of FBXW7. STAT2 phosphorylation at the putative degron motifs that contain Ser381, Thr385, and Ser393 might be mediated by GSK3β. These serve as critical amino acids that form hydrogen bonds with the WD40 domain of FBXW7. Thus, the FBXW7–STAT2 signaling axis is an important target for melanoma treatment.

FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation