WWOX/WOX1 and signaling networks. (A) A schematic structure of WWOX/WOX1 (414 amino acids; molecular size 46 kDa) is shown. Two N-terminal WW domains are encoded by exon 1–4 of the WWOX gene, and the ADH/SDR domain by exon 4–8. There is a NLS (nuclear localization signal) between the two WW domains, and a NSYK motif in the ADH/SDR domain. The C-terminal tail D3 domain possesses an apoptotic function. The conserved phosphorylation sites are indicated [54–63]. (B) WWOX interacts with binding proteins via PPXY motifs. Protein of these categories are p73, activator protein 2γ (AP-2γ), ErbB4, ezrin, small integral membrane protein of the lysosome/late endosome (SIMPLE), c-Jun [59–63]. WWOX is involved in the Wnt/β-catenin pathway and the HGF (hepatocyte growth factor)/MET pathway. WWOX acts synergistically with p53 to mediate apoptosis, and that JNK and Zfra block the effect. Complement C1q induces an unconventional apoptosis of prostate cancer cells [59, 60, 62]. WWOX prevents neurodegeneration by inhibiting Tau hyperphosphorylation caused by ERK and GSK-3β [59, 60, 62]. Hyaluronidase Hyal-2 acts as a receptor for TGF-β1. During signaling, WWOX is activated and binds Smad4 and the protein complex is accumulated in the nucleus, which may lead to cell survival or death [59, 60, 62].