%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.