%A Hsu,Li-Jin %A Chiang,Ming-Fu %A Sze,Chun-I %A Su,Wan-Pei %A Yap,Ye Vone %A Lee,I-Ting %A Kuo,Hsiang-Ling %A Chang,Nan-Shan %D 2016 %J Frontiers in Cell and Developmental Biology %C %F %G English %K Zfra,Peptides,Polymerization,Cancer,hyaluronan,Hyaluronidase,prevention,Treatment,Z cell,Hyal-2 %Q %R 10.3389/fcell.2016.00141 %W %L %M %P %7 %8 2016-December-06 %9 Review %+ Nan-Shan Chang,Institute of Molecular Medicine, College of Medicine, National Cheng Kung University,Tainan, Taiwan,changns@mail.ncku.edu.tw %+ Nan-Shan Chang,Advanced Optoelectronic Technology Center, National Cheng Kung University,Tainan, Taiwan,changns@mail.ncku.edu.tw %+ Nan-Shan Chang,Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University,Tainan, Taiwan,changns@mail.ncku.edu.tw %+ Nan-Shan Chang,Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities,Staten Island, NY, USA,changns@mail.ncku.edu.tw %+ Nan-Shan Chang,Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University,Taichung, Taiwan,changns@mail.ncku.edu.tw %# %! HYAL-2–WWOX–SMAD4 signaling %* %< %T HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response %U https://www.frontiersin.org/articles/10.3389/fcell.2016.00141 %V 4 %0 JOURNAL ARTICLE %@ 2296-634X %X Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-β) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2–WWOX–SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2–WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2–WWOX–SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3 CD19 Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2–WWOX–SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2–WWOX–SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response.