SMAD4 and head and neck squamous cell carcinoma: However, in Head and neck squamous cell carcinoma (HNSCC) cell lines, where DRAK1 is overexpressed, DRAK1 in the cytoplasm binds to Smad3 and sequesters it in the cytoplasm, thereby preventing Smad3/Smad4 complex formation and inhibiting TGF-β1 tumor suppression [23].