The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway

Abstract

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 β‐catenin dependent transcription. We also show that USP4 is a DUB with dual hydrolysing activity for K48‐ and K63‐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.

Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFα-induced cancer cell migration

“…However, reports have also shown the USP4 protein level to be decreased in lung cancer cell lines, and it is not elevated in breast and pancreatic cancer [26,31]. Moreover, USP4 is demonstrated as a negative regulator of the Wnt signalling pathway [32], which has tumorigenic activity [33]. The results of the present study suggest that USP4 is a negative regulator of cell migration of cancer cells.…”

Ubiquitin‐specific protease 4 is inhibited by its ubiquitin‐like domain

“…Identified as a proto‐oncogene related to Tre 2/Tre 17 (USP6), USP4 shows a consistently elevated gene expression level in small cell tumours and lung adenocarcinomas, suggesting that it may have a possible causative role in neoplasia (Gray et al , 1995). Besides possible roles in Wnt signalling (Zhao et al , 2009) and recruitment to the A2A receptor (Milojevic et al , 2006), USP4 is recruited to the spliceosome by complex formation with Sart3 (Song et al , 2010). Here, it preferentially deubiquitinates K63‐linked chains on the U4 component Prp3.…”

USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1

“…In addition to the p53 pathways, USP4 appears to function in other key regulatory pathways. A recent study reported that knockdown of USP4 activated β‐catenin‐associated transcription (Zhao et al , 2009a). By interacting with two known Wnt signalling components: Nemo‐like kinase and T‐cell factor 4, USP4 may integrate into canonical Wnt signalling in a variety of physiological and pathological conditions.…”