General
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CDH1 (also known as E-cadherin, epithelial cadherin, Cadherin-1, CADH1, or uvomorulin) undergoes evolutionarily conserved O-mannosylation on multiple serine and threonine residues in its ectodomains (cadherin domains) 2 to 5 in the endoplasmic reticulum (Lommel et al. 2013; Vester-Christensen et al. 2013; Carvalho et al. 2016; Larsen et al. 2017; Graham et al. 2020). O-mannosylation of CDH1, the major cell-adhesion molecule in mouse blastomeres, was first reported to be crucial for cadherin-based cell adhesion during early mouse embryonic development (Lommel et al. 2013). Mouse embryos knockout for either POMT1 or POMT2, two endoplasmic reticulum O-mannosyltransferases that function as the POMT1:POMT2 complex, are O-mannosylation-deficient and die early during development (Lommel et al. 2013). Pomt1 knockout embryos do form blastocysts but die immediately upon implantation, while Pomt2 knockout embryos fail to progress from the morula to the blastocyst stage (Lommel et al. 2013). This difference is possibly due to a higher level of maternal Pomt1 mRNA than maternal Pomt2 mRNA in mouse eggs, which results in a temporary compensation of the Pomt1 gene loss (Lommel et la. 2013). Inhibition of O-mannosylation negatively affects cell-cell aggregation in the canine MDCK kidney-derived cell line, where mannosylation of both E-cadherin and K-cadherin is affected (Lommel et al. 2013). O-linked mannose residues on CDH1 are not elongated further (Lommel et al. 2013; Vester-Christensen et al. 2013; Larsen et al. 2017). Cadherins, including CDH1, as well as related protocadherins, were found to be one of the major carriers of O-Man glycans, with 37 cadherins/protocadherins identified as O-Man glycans in the human breast cancer cell line MDA-MB-231 (Vester-Christensen et al. 2013). While the consensus sequence of the O-mannosylated serine/threonine residues has not been established, mass spectrometry has identified evolutionarily conserved CDH1 O-mannosylated residues at S280, T285, T358, T470, T472, T509, T576, T578, and T580 that are shared with at least one of the other related Cadherin type I subfamily members (Vester-Christensen et al. 2013: in this paper, the amino acid residues are counted using the first amino acid in the mature CDH1 as the start coordinate, which represents amino acid 155 in the nascent protein, so that the aforementioned residues correspond to residues S126, T131, T204, T316, T318, T355, T422, T424, and T426 in the paper, respectively). O-mannosylation of CDH1 is significantly reduced in gastric carcinoma compared with the adjacent normal gastric mucosa (Carvalho et al. 2016). Reduced CDH1 expression and mislocalization in the human gastric cancer cell line Kato III is associated with reduced mRNA and protein levels of POMT1 (Carvalho et al. 2016). POMT2 knockdown in human gastric carcinoma cells reduces CDH1 stability at the plasma membrane, localization to cell-cell borders, and the association with CTNND1 (also known as p120 catenin or delta catenin) (Carvalho et al. 2016). CDH1 can still undergo O-mannosylation in the absence of POMT1 and POMT2 (Larsen et al. 2017), and another endoplasmic reticulum O-mannosyltransferase, TMTC3, was reported to contribute to CDH1 O-mannosylation (Graham et al. 2020).
