Ubiquitin Specific Protease 34 (USP34), a New Positive Regulator of Canonical Wnt/β-catenin Signalling

The Wnt pathway is a fundamental signalling pathway conserved in all animals, regulating growth, differentiation, embryonic development, and tissue homeostasis in adults. Wnt signalling is kept quiescent by ubiquitin-mediated degradation of the transcription factor β-catenin, orchestrated by a group of proteins called the Destruction Complex. Aberrant Destruction Complex activity is a common theme in many cancers, and is the primary cause of colon cancer. Through mass spectrometry analysis of Axin protein complexes (a key Destruction Complex component) we identified the deubiquitinating enzyme USP34 as an Axin-interacting protein. Functional studies showed USP34 functions to positively regulate Wnt signalling, acting downstream of β-catenin stabilization. While characterizing USP34 we also discovered a new positive regulatory role for Axin in promoting signalling that is dependent on its nuclear localization. Our results suggest that USP34 stabilizes the nuclear pool of Axin through regulating its ubiquitination and offers a potential strategy to target pathological Wnt signalling.MAS