Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed
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Li-Jin Hsu1,3,*, Qunying Hong1,*, Shur-Tzu Chen1,4,*, Hsiang-Lin Kuo2,*, Lori Schultz1, John Heath1, Sing-Ru Lin2, Ming-Hui Lee2, Dong-Zhang Li2, Zih-Ling Li2, Hui-Ching Cheng3, Gerard Armand7, Nan-Shan Chang1,2,5,6
1Guthrie Research Institute, Laboratory of Molecular Immunology, Sayre, PA, USA
2Institute of Molecular Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan, ROC
3Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University College of Medicine, Tainan, Taiwan, ROC
4Department of Cell Biology and Anatomy, National Cheng Kung University College of Medicine, Tainan, Taiwan, ROC
5Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan, Taiwan, ROC
6Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan, ROC
7Glycomed Research Inc., Hastings on Hudson, New York, NY, USA
*Equal contributions among these authors
Nan-Shan Chang, email: [email protected]
Keywords: hyaluronan, hyaluronidase, Hyal-2, Smad, WWOX
Received: April 08, 2016 Accepted: October 17, 2016 Published: November 10, 2016
Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.
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