Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Cleavage and cell adhesion properties of human epithelial cell adhesion molecule (HEPCAM)

J Biol Chem. 2015 Oct 2;290(40):24574-91.

Authors/Editors: Tsaktanis T
Kremling H
Pavsic M
von Stackelberg R
Mack B
Steiner H
Vielmuth F
Spindler V
Huang Z
Jakubowski J
Stoecklein NH
Luxenburger E
Lauber K
Lenarcic B
Gires O
Type of Publication: Journal Article

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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