A mechanism for inhibition of E-cadherin-mediated cell-cell adhesion by the membrane-associated mucin episialin/MUC1.
Episialin (MUC1, PEM, EMA, CA15-3 antigen) is a sialylated, membrane-associated glycoprotein with an extended mucin-like ectodomain. This domain mainly consists of 30-90 homologous 20-amino acid repeats that are rich in O-glycosylation sites (serines and threonines). It is likely that this part forms a polyproline beta-turn helix. As a result, the ectodomain can protrude more than 200 nm above the cell surface, whereas most cell surface molecules do not exceed a length of 35 nm. Normally, episialin is present at the apical side of glandular epithelial cells. On carcinoma cells, however, it can be strongly overexpressed and it is often present over the entire cell surface. We have previously shown that episialin, if it is interspersed between adhesion molecules, nonspecifically reduces cell-cell and cell-extracellular matrix interactions in vitro and in vivo, presumably by steric hindrance caused by the extreme length and high density of the episialin molecules at the cell surface. To analyze the molecular mechanism for this anti-adhesion effect in more detail, we have now deleted an increasing number of repeats in the episialin cDNA and transfected the resulting mutants into murine L929 cells expressing the homophilic adhesion molecule E-cadherin. Here we show that the length of episialin is the dominant factor that determines the inhibition of E-cadherin-mediated cell-cell interactions. For the anti-adhesive effect mediated by the full length episialin, charge repulsion by negatively charged sialylated O-linked glycans is far less important.
Wesseling
J
J
Department of Tumor Biology, The Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Amsterdam.
van der Valk
S W
SW
Hilkens
J
J
D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology*; D015153:Blotting, Western; D015820:Cadherins / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000032:analysis; D051379:Mice; D018396:Mucin-1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D019158:N-Acetylneuraminic Acid; D015183:Restriction Mapping; D017384:Sequence Deletion; D012794:Sialic Acids / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D000951:Antigens, Neoplasm; D015820:Cadherins; D018076:DNA, Complementary; D018396:Mucin-1; D012794:Sialic Acids; D019158:N-Acetylneuraminic Acid