Ectopic overexpression of a recombinant mouse CBLL1 (Hakai), an E3 ubiqutin ligase, in the canine cell line MDCK, promotes the internalization of the endogenous CDH1 (E-cadherin) through endocytosis and shortens the half-life of CDH1, leading to loss of adherens junctions and cell scattering (Fujita et al. 2002). ARF6, RAB5, and RAB7 are involved in trafficking of recombinant mouse CDH1 to lysosome for degradation in MDCK cells upon SRC-facilitated tyrosine phosphorylation and ubiquitination of CDH1 (Palacios et al. 2005). In the human breast cancer cell line MCF7, calcium depletion-triggered activation of CDC42 RHO GTPase and SRC kinase correlates with increased CBLL1-dependent ubiquitination and internalization that leads to lysosome-dependent degradation of CDH1, while the proteasome did not appear to play a significant role in CDH1 degradation downstream of CBLL1-mediated ubiquitination (Shen et al. 2008). In the human hepatocellular carcinoma cell line HepG2, activation of SRC and FYN kinases correlates with increased binding of CBLL1 to CDH1 and increased CDH1 ubiquitination and internalization, leading to CDH1 degradation through both proteasomal and lysosomal route (Chen et al. 2009). In a study in which recombinant mouse CDH1 constructs, either full-length or just involving the juxtamembrane domain (JMD) of CDH1, were expressed in the canine MDCK cell line, it was found that the proteasome is at least partially responsible for degradation of the ubiquitinated CDH1 (Hartsock and Nelson 2012). In the human colon carcinoma cell line T84, IFNG (interferon γ)-stimulated internalization of CDH1 is dependent on FYN kinase and CBLL1, and both the lysosome and the proteasome contribute to degradation of internalized CDH1 (Smyth et al. 2012). RAF kinase may promote the sorting of internalized CDH1 from the endosome to the lysosome compartment rather than to the recycling route (Janda et al. 2006).