PTEN is one of the most frequently mutated or deleted tumor suppressors in human 
cancers. NEDD4-1 was recently identified as the E3 ubiquitin ligase for PTEN; 
however, a number of important questions remain regarding the role of 
ubiquitination in regulating PTEN function and the mechanisms by which PTEN 
ubiquitination is regulated. In the present study, we demonstrated that p34, 
which was identified as a binding partner of NEDD4-1, controls PTEN 
ubiquitination by regulating NEDD4-1 protein stability. p34 interacts with the 
WW1 domain of NEDD4-1, an interaction that enhances NEDD4-1 stability. 
Expression of p34 promotes PTEN poly-ubiquitination, leading to PTEN protein 
degradation, whereas p34 knockdown results in PTEN mono-ubiquitination. Notably, 
an inverse correlation between PTEN and p34/NEDD4-1 levels was confirmed in 
tumor samples from colon cancer patients. Thus, p34 acts as a key regulator of 
the oncogenic behavior of NEDD4-1 and PTEN.