In a non-canonical pathway, transforming growth factor beta (TGF-β) binds membrane Hyal-2 and then recruits tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 induces SMAD-dependent transcriptional activation in the nucleus [18, 21, 22]. The gene discussed is WWOX; the disease is neoplasm.