Open AccessThe ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway
Author(s) -
Binghao Zhao,
Claudia Schlesiger,
Maria G. Masucci,
Kristina Lindsten
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00682.x
Subject(s) - wnt signaling pathway , microbiology and biotechnology , deubiquitinating enzyme , biology , lrp5 , ubiquitin , rna interference , transcription factor , lrp6 , signal transduction , chemistry , biochemistry , rna , gene
The canonical Wnt signalling pathway is essential for cell fate determination during embryonic development and for the maintenance of adult tissue homeostasis. Deregulation of Wnt signalling leads to developmental defects and is associated with various types of cancer. Here we have used an RNA interference (RNAi) library specifically targeting human deubiquitinating enzymes (DUBs) to screen for new regulators of the canonical Wnt signalling pathway. We found that suppression of the ubiquitin specific protease 4 (USP4) activates beta-catenin dependent transcription. We also show that USP4 is a DUB with dual hydrolysing activity for K(48)- and K(63)-conjugated polyubiquitin chains and interacts with two known Wnt signalling components: the Nemo like kinase (Nlk) and the transcription factor (T-cell factor 4 [TCF4]). Overexpression of a catalytically active Nlk promotes nuclear accumulation of USP4 whereas a subpopulation of TCF4 is a substrate of USP4-dependent deubiquitination. Thus, modulation of USP4 expression may provide a new means to interfere with canonical Wnt signalling in a variety of physiological and pathological conditions.