Reactome | Regulation of CDH1 posttranslational processing and trafficking to plasma membrane

Regulation of CDH1 posttranslational processing and trafficking to plasma membrane

Stable Identifier

R-HSA-9768727

Type

Pathway

Species

Homo sapiens

ReviewStatus

3/5

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Cell-Cell communication (Homo sapiens)

- Cell junction organization (Homo sapiens)
  - Cell-cell junction organization (Homo sapiens)
    - Adherens junctions interactions (Homo sapiens)
      - Regulation of Homotypic Cell-Cell Adhesion (Homo sapiens)
        
        Regulation of Expression and Function of Type I Classical Cadherins (Homo sapiens)
        
        Regulation of CDH1 Expression and Function (Homo sapiens)
        
        Regulation of CDH1 posttranslational processing and trafficking to plasma membrane (Homo sapiens)

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Regulation of CDH1 posttranslational processing and trafficking to plasma membrane

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CDH1 (also known as E-cadherin, epithelial cadherin, Cadherin-1, CADH1, or uvomorulin) is synthesized as a precursor protein of ~140 kDa (Shore and Nelson 1991). The N-terminal signal peptide (amino acid residues 1-22) is removed in the endoplasmic reticulum (ER), while the proprotein region (amino acid residues 23-154) of CDH1 is cleaved in the trans-Golgi network, resulting in a protein of ~120 kDa. While proteolytic cleavage is not necessary for CDH1 presentation at the plasma membrane, it is necessary for the establishment of homotypic interactions at adhesion junctions (Ozawa and Kemler 1990; Shore and Nelson 1991). The proprotein sequence of CDH1 is predominantly removed by FURIN, but other proprotein convertases are also involved (Posthaus et al. 1998). Like other plasma membrane proteins, CDH1 undergoes glycosylation on multiple amino acid residues. Four glycosylated asparagines in CDH1 conform with the glycosylation sequon Asn-X-Thr/Ser which is glycosylated in the endoplasmic reticulum (ER) through transfer of the preassembled, high-mannose oligosaccharide, Glu3Man9GlucNAc2 glycan, from a dolichyl-pyrophosphate carrier by the oligosaccharyltransferase (OST) complex (Ramírez et al. 2019). N-glycosylation of CDH1 on four asparagine residues, and N637 in particular, is required for proper folding and translocation of CDH1 to Golgi for further processing (Zhou et al. 2008; Zhao H. et al. 2008). In Drosophila, the glucosyltransferase Xiantuan (also known as xit, a homologue of yeast ALG8), which encodes one of the enzymes involved in the addition of the terminal glucose residues to the Glu3Man9GlucNAc2 glycan precursor, is required for the proper glycosylation and intracellular distribution of E-cadherin (Zhang et al. 2014). CDH1 also undergoes O-mannosylation in the ER, with TMTC3 as one of the implicated ER mannosyltransferases (Graham et al. 2020). CDH1 associates with beta-catenin (CTNNB1) during posttranslational processing in the ER (Chen et al. 1999). In the Golgi, CDH1 may undergo additional glycosylation catalyzed by GALNT3, which transfers O-GalNAc group to target proteins (Wang et al. 2014; Raghu et al. 2019; Shu et al. 2023). During apoptosis, ER stress was reported to lead to O-glycosylation of both CTNNB1 and the CDH1 cytosolic tail, blocking exit of CDH1 from the ER, and reducing intercellular adhesion (Zhu et al. 2001; Geng et al. 2012). Trafficking of CDH1 to the plasma membrane from Golgi is negatively regulated by RAB2A (Kajiho et al. 2016). Golgi membrane protein TMEM165 was also reported to negatively regulate CDH1 trafficking to the plasma membrane by affecting CDH1 glycosylation (Murali et al. 2020). CDH1 glycosylation was found to be altered in cancer (Yoshimura et al. 1996; Byrne et al. 2012; reviewed in Zhao Y. et al. 2008; reviewed in Bastian et al. 2021), which can have an effect on CTNNB1 signaling (Kitada et al. 2001). Cell type-specific processing of CDH1 has also been reported (Burke and Hong 2006). Trafficking of CDH1 to the cell surface can be regulated in a cell confluency-dependent manner, so that subconfluent cells present less CDH1 on their surface (Murray et al. 2004). Glycosylation of CDH1 was also reported to differ between confluent and subconfluent cells (Liwosz et al. 2006).

Literature References

PubMed ID	Title	Journal	Year
32733646	Novel role for the Golgi membrane protein TMEM165 in control of migration and invasion for breast carcinoma Murali, P, Johnson, BP, Lu, Z, Climer, L, Scott, DA, Foulquier, F, Oprea-Ilies, G, Lupashin, V, Drake, RR, Abbott, KL	Oncotarget	2020
27255086	RAB2A controls MT1-MMP endocytic and E-cadherin polarized Golgi trafficking to promote invasive breast cancer programs Kajiho, H, Kajiho, Y, Frittoli, E, Confalonieri, S, Bertalot, G, Viale, G, Di Fiore, PP, Oldani, A, Garré, M, Beznoussenko, GV, Palamidessi, A, Vecchi, M, Chavrier, P, Perez, F, Scita, G	EMBO Rep	2016
31831667	Cryo-electron microscopy structures of human oligosaccharyltransferase complexes OST-A and OST-B Ramírez, AS, Kowal, J, Locher, KP	Science	2019
30917321	GALNT3 Maintains the Epithelial State in Trophoblast Stem Cells Raghu, D, Mobley, RJ, Shendy, NAM, Perry, CH, Abell, AN	Cell Rep	2019
8662832	Aberrant glycosylation of E-cadherin enhances cell-cell binding to suppress metastasis Yoshimura, M, Ihara, Y, Matsuzawa, Y, Taniguchi, N	J Biol Chem	1996
22223758	Deoxycholic acid impairs glycosylation and fucosylation processes in esophageal epithelial cells Byrne, AM, Sharma, R, Duggan, G, Kelleher, D, Long, A	Glycobiology	2012
10037790	Coupling assembly of the E-cadherin/beta-catenin complex to efficient endoplasmic reticulum exit and basal-lateral membrane targeting of E-cadherin in polarized MDCK cells Chen, YT, Stewart, DB, Nelson, WJ	J Cell Biol	1999
18384383	Branched N-glycans regulate the biological functions of integrins and cadherins Zhao, Y, Sato, Y, Isaji, T, Fukuda, T, Matsumoto, A, Miyoshi, E, Gu, J, Taniguchi, N	FEBS J	2008
31851597	Endoplasmic reticulum transmembrane protein TMTC3 contributes to O-mannosylation of E-cadherin, cellular adherence, and embryonic gastrulation Graham, JB, Sunryd, JC, Mathavan, K, Weir, E, Larsen, ISB, Halim, A, Clausen, H, Cousin, H, Alfandari, D, Hebert, DN	Mol Biol Cell	2020
1918074	Biosynthesis of the cell adhesion molecule uvomorulin (E-cadherin) in Madin-Darby canine kidney epithelial cells Shore, EM, Nelson, WJ	J Biol Chem	1991
24681004	The glucosyltransferase Xiantuan of the endoplasmic reticulum specifically affects E-Cadherin expression and is required for gastrulation movements in Drosophila Zhang, Y, Kong, D, Reichl, L, Vogt, N, Wolf, F, Großhans, J	Dev Biol	2014
14742711	The FAM deubiquitylating enzyme localizes to multiple points of protein trafficking in epithelia, where it associates with E-cadherin and beta-catenin Murray, RZ, Jolly, LA, Wood, SA	Mol Biol Cell	2004
22375065	Multiple post-translational modifications regulate E-cadherin transport during apoptosis Geng, F, Zhu, W, Anderson, RA, Leber, B, Andrews, DW	J Cell Sci	2012
17979184	N-glycosylation affects the adhesive function of E-Cadherin through modifying the composition of adherens junctions (AJs) in human breast carcinoma cell line MDA-MB-435 Zhao, H, Liang, Y, Xu, Z, Wang, L, Zhou, F, Li, Z, Jin, J, Yang, Y, Fang, Z, Hu, Y, Zhang, L, Su, J, Zha, X	J Cell Biochem	2008
11689440	Cytoplasmic O-glycosylation prevents cell surface transport of E-cadherin during apoptosis Zhu, W, Leber, B, Andrews, DW	EMBO J	2001
16682414	N-glycosylation affects the molecular organization and stability of E-cadherin junctions Liwosz, A, Lei, T, Kukuruzinska, MA	J Biol Chem	2006
11024053	The addition of bisecting N-acetylglucosamine residues to E-cadherin down-regulates the tyrosine phosphorylation of beta-catenin Kitada, T, Miyoshi, E, Noda, K, Higashiyama, S, Ihara, H, Matsuura, N, Hayashi, N, Kawata, S, Matsuzawa, Y, Taniguchi, N	J Biol Chem	2001
33466384	FUT8 Alpha-(1,6)-Fucosyltransferase in Cancer Bastian, K, Scott, E, Elliott, DJ, Munkley, J	Int J Mol Sci	2021
18491227	Unglycosylation at Asn-633 made extracellular domain of E-cadherin folded incorrectly and arrested in endoplasmic reticulum, then sequentially degraded by ERAD Zhou, F, Su, J, Fu, L, Yang, Y, Zhang, L, Wang, L, Zhao, H, Zhang, D, Li, Z, Zha, X	Glycoconj J	2008
37046045	Exosomal circSPIRE1 mediates glycosylation of E-cadherin to suppress metastasis of renal cell carcinoma Shu, G, Lu, X, Pan, Y, Cen, J, Huang, K, Zhou, M, Lu, J, Dong, J, Han, H, Chen, W, Lin, J, Luo, J, Zhang, J	Oncogene	2023
2211831	Correct proteolytic cleavage is required for the cell adhesive function of uvomorulin Ozawa, M, Kemler, R	J Cell Biol	1990
9827567	Proprotein cleavage of E-cadherin by furin in baculovirus over-expression system: potential role of other convertases in mammalian cells Posthaus, H, Dubois, CM, Laprise, MH, Grondin, F, Suter, MM, Müller, E	FEBS Lett	1998
16877438	Fate of E-cadherin in early RPE cultures: transient accumulation of truncated peptides at nonjunctional sites Burke, JM, Hong, J	Invest Ophthalmol Vis Sci	2006
24504219	Role of the polypeptide N-acetylgalactosaminyltransferase 3 in ovarian cancer progression: possible implications in abnormal mucin O-glycosylation Wang, ZQ, Bachvarova, M, Morin, C, Plante, M, Gregoire, J, Renaud, MC, Sebastianelli, A, Bachvarov, D	Oncotarget	2014