NEDD4L and melanoma: However, the projected effects of such possible role in BRAF-mutant melanoma are contradictory: NEDD4L-mediated SMAD2/3 degradation would lead to the termination of TGFβ signaling rather than its activation28, while previous reports have shown that TGFβ signaling upregulates the EGFR pathway to confer resistance to BRAF inhibition in melanoma9.