Characterizing WW domain interactions of tumor suppressor WWOX reveals its association with multiprotein networks

Mohammad Abu-Odeh, Tomer Bar-Mag, Haiming Huang, Tae Hyung Kim, Zaidoun Salah, Suhaib K. Abdeen, Marius Sudol, Dana Reichmann, Sachdev Sidhu, Philip M. Kim, Rami I. Aqeilan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations


WW domains are small modules present in regulatory and signaling proteins that mediate specific protein-protein interactions. The WW domain-containing oxidoreductase (WWOX) encodes a 46-kDa tumor suppressor that contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase domain. Based on its ligand recognition motifs, the WW domain family is classified into four groups. The largest one, to which WWOX belongs, recognizes ligands with a PPXY motif. To pursue the functional properties of the WW domains of WWOX, we employed mass spectrometry and phage display experiments to identify putative WWOX-interacting partners. Our analysis revealed that the first WW (WW1) domain of WWOX is the main functional interacting domain. Furthermore, our study uncovered well known and new PPXY-WW1-interacting partners and shed light on novel LPXY-WW1-interacting partners of WWOX. Many of these proteins are components of multiprotein complexes involved in molecular processes, including transcription, RNA processing, tight junction, and metabolism. By utilizing GST pull-down and immunoprecipitation assays, we validated that WWOX is a substrate of the E3 ubiquitin ligase ITCH, which contains two LPXY motifs. We found that ITCH mediates Lys-63-linked polyubiquitination of WWOX, leading to its nuclear localization and increased cell death. Our data suggest that the WW1 domain of WWOX provides a versatile platform that links WWOX with individual proteins associated with physiologically important networks.

Original languageAmerican English
Pages (from-to)8865-8880
Number of pages16
JournalJournal of Biological Chemistry
Issue number13
StatePublished - 30 Mar 2014


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