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Regulation of CDH1 posttranslational processing and trafficking to plasma membrane

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-9768727

PubChem

R-HSA-9768727

Description

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).

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SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying entries **1 - 10** of 23 in total

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UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
A7KAX9	Rho GTPase-activating protein 32	ARHGAP32 GRIT KIAA0712 RICS	view
O60331	Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma	KIAA0589 PIP5K1C	view
P04843	Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1	RPN1	view
P04844	Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 2	RPN2	view
P09958	Furin	FUR FURIN PACE PCSK3	view
P12830	Cadherin-1	CDH1 CDHE UVO	view
P14314	Glucosidase 2 subunit beta	G19P1 PRKCSH	view
P14923	Junction plakoglobin	CTNNG DP3 JUP	view
P19784	Casein kinase II subunit alpha'	CK2A2 CSNK2A2	view
P27824	Calnexin	CANX	view

Displaying **all 3** entries
GlyCosmos Lectin	UniProt ID	Lectin Name	Pathway Viewer
GL_000249	P27824	Calnexin	view
GL_001725	Q14697	Neutral alpha-glucosidase AB	view
GL_005344	P12830	Cadherin-1	view

Displaying 1 entry
GlyTouCan ID	KEGG GLYCAN	ChEBI	Pathway Viewer
G71142DF	G10238 G10618 G12561 G13015	15903	view

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