However, studies conducted in NEDD4 knock out (KO) mice showed that PTEN stability was not affected by the E3 ligase deficiency (Fouladkou et al., 2008), while others showed that overexpression of NEDD4 in colorectal cancers promotes cancer cell growth independently of PTEN and PI3K/AKT signaling, arguing that NEDD4-mediated regulation of PTEN is microenvironment and/or cell-type specific, and that other yet-unknown substrates are implicated in the process (Eide et al., 2013). This evidence concerns the gene NEDD4 and cancer.