Correct proteolytic cleavage of the proprotein of CDH1 (E...

Correct proteolytic cleavage of the proprotein of CDH1 (E-cadherin) is required for its adhesive function but not for association with alpha-, gamma-, and beta-catenins, nor for the presentation at the plasma membrane (Ozawa and Kemler 1990). The proprotein cleavage site sequence in CDH1, the RQKR (Arg-Gln-Lys-Arg) motif after which the cleavage occurs, is evolutionarily conserved (Ozawa and Kemler 1990), and corresponds to the FURIN consensus cleavage site (Posthaus et al. 1998). In insect cells expressing recombinant mouse CDH1 in which proprotein is not efficiently removed, co-expression of recombinant human FURIN enables proprotein cleavage (Pothouse et al. 1998). In human breast cancer cell line MCF7, FURIN inhibitors prevent proprotein removal from CDH1 (Geng et al. 2012). In the human colon carcinoma cell line Lo-Vo, which is FURIN-deficient, CDH1 proprotein is properly removed, suggesting that other Golgi proprotein convertases contribute to CDH1 processing (Posthaus et al. 1998). In human HepG2 cell line, siRNA-mediated knockdown of FURIN or PCSK7 (PC7) or the use of FURIN inhibitors all decrease CDH1 proprotein cleavage (Bessonnard et al. 2015). PCSK6 (PACE4) is able to partially compensate CDH1 proprotein cleavage in mouse embryonic cells in which Furin and Pcsk7 genes have been knocked out (Bessonnard et al. 2015). Both recombinant mouse PC7 (PCSK7) and recombinant mouse FURIN were shown to localize to the trans-Golgi network (TGN) in human cell lines and cleave the proprotein of recombinant mouse CDH1 (Ginefra et al. 2018).

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 CDH1 bound to JUP would undergo proteolytic processing in the Golgi. Different cell types show different ratios of CDH1:CTNNB1 and CDH1:JUP complexes (Butz and Kemler 1994).