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Cleavage and cell adhesion properties of Human Epithelial Cell Adhesion Molecule (HEPCAM).
J. Biol. Chem. 290, 24574-24591 (2015)
Human epithelial cell adhesion molecule (HEPCAM) is a tumor-associated antigen frequently expressed in carcinomas, which promotes proliferation after regulated intramembrane proteolysis. Here, we describe extracellular shedding of HEPCAM at two α-sites through a disintegrin and metalloprotease (ADAM) and at one β-site through BACE1. Transmembrane cleavage by γ-secretase occurs at three γ-sites to generate extracellular Aβ-like fragments and at two ϵ-sites to release human EPCAM intracellular domain HEPICD, which is efficiently degraded by the proteasome. Mapping of cleavage sites onto three-dimensional structures of HEPEX cis-dimer predicted conditional availability of α- and β-sites. Endocytosis of HEPCAM warrants acidification in cytoplasmic vesicles to dissociate protein cis-dimers required for cleavage by BACE1 at low pH values. Intramembrane cleavage sites are accessible and not part of the structurally important transmembrane helix dimer crossing region. Surprisingly, neither chemical inhibition of cleavage nor cellular knock-out of HEPCAM using CRISPR-Cas9 technology impacted the adhesion of carcinoma cell lines. Hence, a direct function of HEPCAM as an adhesion molecule in carcinoma cells is not supported and appears to be questionable.
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Publication type
Article: Journal article
Document type
Scientific Article
Language
english
Publication Year
2015
HGF-reported in Year
0
ISSN (print) / ISBN
0021-9258
e-ISSN
1083-351X
Quellenangaben
Volume: 290,
Issue: 40,
Pages: 24574-24591
Publisher
American Society for Biochemistry and Molecular Biology
Reviewing status
Peer reviewed
Institute(s)
Translational Metabolic Oncology (IDC-TMO)
POF-Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s)
Radiation Sciences
PSP Element(s)
G-521800-001
PubMed ID
26724312
PubMed ID
26292218
Erfassungsdatum
2015-12-31