CDH1 (E-cadherin) is targeted to the basolateral plasma membrane after processing in Golgi (Miranda et al. 2003). While CTNNB1 translocates to the basolateral membrane as a part of the complex with CDH1, CTNNB1 per se is not sufficient for targeting of CDH1 to the basolateral membrane, as demonstrated in experiments in which human CDH1 was expressed in canine MDCK cell line (Miranda et al. 2003). A dileucine sorting motif located in the juxtamembrane region of CDH1 is needed for its basolateral membrane localization, and in the absence of it the complex of CDH1 and CTNNB1 gets targeted to the apical membrane (Miranda et al. 2003). RAB2A was reported to negatively regulate trafficking on CDH1 from Golgi to the plasma membrane (Kajiho et al. 2016). A Golgi membrane protein TMEM165 was reported to negatively affect trafficking of CDH1 from Golgi to plasma membrane by altering the CDH1 glycosylation pattern (Murali et al. 2020).
JUP (commonly known as Plakoglobin or gamma-catenin) was first reported to associate with CDH1 in the mouse NIH3T3 cell line (Ozawa et al. 1989), and then in the canine MDCK cell line (Reynolds et al. 1994). In human cancer cell line A431, it was shown that binding of JUP to CDH1 is mutually exclusive with CTNNB1 binding to CDH1 (Butz and Kemler 1994; Chitaev and Troyanovsky 1998). While the role of JUP in CDH1 posttranslational processing has not been studied, it was found, in a study using human breast cancer cell lines, that O-glycosylation of the cytosolic tail of CDH1 in apoptosis, which prevents its trafficking to the plasma membrane, does not interfere with its binding to JUP (Zhu et al. 2001), suggesting that JUP associates with CDH1 at a similar point as CTNNB1, so that the CDH1:JUP complex would traffick from Golgi to the plasma membrane. Different cell types show different ratios of CDH1:CTNNB1 and CDH1:JUP complexes (Butz and Kemler 1994).
Recombinant human CDH1 deficient for ANK3 binding is retained in Golgi when expressed in HBE cells (Kizhatil et al. 2007). ANK3 likely couples CDH1 to spectrin, which then facilitates transport of CDH1 to the plasma membrane via microtubule-dependent post-Golgi carriers (Kizhatil et al. 2007).
Binding to PIP5K1C (commonly known as PIPKIgamma, or Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma) positively regulates trafficking of CDH1 from Golgi to the basolateral membrane (Ling et al. 2007). PIP5K1C catalytic activity is needed for facilitation of CDH1 trafficking (Ling et al. 2007; Xiong et al. 2012). PIP5K1C is thought to first promote trafficking of CDH1 to recycling endosomes, which serve as a putative intermediary destination for proteins whose final destination is the basolateral plasma membrane (Ling et al. 2007). As O-glycosylation of the cytosolic tail of CDH1 during apoptosis both interferes with trafficking of CDH1 from ER to Golgi and prevents binding of PIP5K1C to CDH1, it is possible that PIPK1C associates with CDH1 while it is still undergoing processing in the ER (Geng et al. 2012). Different splicing isoforms of PIP5K1C may differ in their affinity for CDH1 and specificity for different trafficking routes and the canonical isoform of 661 amino acids in mouse and 668 amino acids in humans is the best characterized in the above described process (Ling et al. 2007). PIP5K1C was reported to act by linking clathrin adaptor protein (AP) complexes to CDH1, but details of this mechanism require further elucidation (Ling et al. 2007). PIP5K1C was reported to link CDH1 to the exocyst complex, which is involved in targeting of CDH1 to the basolateral plasma membrane (Xiong et al. 2012). PIP5K1C splicing isoform of 707 amino acids was reported to, instead of promoting trafficking of CDH1 to the plasma membrane, promote lysosomal degradation of CDH1 in response to SRC kinase activation (Schill et al. 2014).
