TGFB1 and melanoma: However, in later stage melanoma cells when TGFβ signaling is high, EWI-2 is downregulated, which allows its two tetraspanin partners CD9 and CD81 to engage with TGFβ receptors and stabilize a signaling active TGFβ receptor complex resulting in increased Smad signaling [56] (Fig. 4).