Schematic diagrams of WWOX structure and its role in signaling. WWOX contains two N-terminal WW domains, a C-terminal short-chain alcohol dehydrogenase/reductase (SDR) domain, and a D3 region. A nuclear localization signal (NLS) is in between the WW domains (Chang et al., 2003, 2007; Del Mare et al., 2011; Salah et al., 2012; Su et al., 2012; reviews). The SDR domain possesses a mitochondria-binding region. There are two conserved tyrosine phosphorylation sites, Tyr33 and Tyr287. Other phosphorylation sites predicted by NetPhos 2.0 Server are Tyr6, Thr12, Ser14, Tyr61, Tyr293, and Thr3B3, respectively. Upon stress stimulation, WWOX is phosphorylated in Tyr33 and binds p53. The WWOX/p53 complex then translocates to mitochondria or nucleus to induce apoptosis. WWOX also binds PPxY motif-containing transcription factors, such as RUNX2, c-Jun, and ERBB4, via its first WW domain, and the binding blocks the activity of these proteins by retaining them in the cytoplasm. WWOX binds Tau via its SDR domain. WWOX participates in the Wnt/β-catenin signal pathway by binding Dvl and inhibiting its nuclear import. Phorbol ester stimulates the dissociation of MEK/WWOX complex in Jurkat T cell, and the released WWOX translocates to the mitochondria for causing cell death. WWOX is recruited to the membrane area by association with Hyal-2 and phospho-Ezrin. Hyal-2 is an alternative receptor for TGF-β1. In response to TGF-β1, WWOX binds Hyal-2 and forms a complex, followed by relocating to the nucleus and enhancing the SMAD-driven promoter activity. Ack1, activated Cdc42-associated kinase 1; Hyal-2, hyaluronoglucosaminidase 2; CKI, casein kinase; GSK, glycogen synthase kinase; PKA, protein kinase A.