In addition, exogenous Zfra peptide binds membrane Hyal-2, and this binding appears to activate the Hyal-2/WWOX/Smad4 signaling in a novel CD3-CD19-Hyal-2+ Z lymphocyte for activation and suppression of cancer growth in vivo [30,42,43] and restoration of memory loss in the brain of triple transgenic mouse for Alzheimer′s disease [31]. Here, SMAD4 is linked to early-onset autosomal dominant Alzheimer disease.