HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Abstract

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.

Zfra restores memory deficits in Alzheimer's disease triple‐transgenic mice by blocking aggregation of TRAPPC6AΔ, SH3GLB2, tau, and amyloid β, and inflammatory NF‐κB activation

“…We do not exclude the possibility that a small amount of Zfra goes through the blood–brain barrier and targets tau or Aβ for accelerating degradation. A portion of WWOX is present on the cell membrane via interacting with Hyal-2 and Ezrin [25] , [27] , [41] , [42] , [43] . Zfra activates Z cells in the spleen probably via the Hyal-2/WWOX/Smad4 pathway [25] , [27] , [41] , [42] .…”

Pleiotropic tumor suppressor functions of WWOX antagonize metastasis

“…One prominent way that WWOX exerts its tumor suppressor activity is through inhibition of the TGFβ pathway. 42,43 Another study has shown that protein-protein interaction between WWOX, through its WW1 domain, and the PPGY motif of SMAD3, leads to the inhibition of SMAD3 transcriptional activity. 44 Moreover, the TGFβ pathway was among the significant altered pathways upon introducing WWOX expression in MDA-MB435S cells (Supplementary Table 2).…”

Functional role of WW domain‐containing proteins in tumor biology and diseases: Insight into the role in ubiquitin‐proteasome system

“…Signaling: WWOX and transcriptional regulation with many transcriptional factors Hyal‐2/ WWOX/Smad4 signaling WWOX/p53 signaling Apoptosis, autophagy, and bubbling cell death …”