NCAM regulates cell motility.
Cell migration is required during development of the nervous system. The regulatory mechanisms for this process, however, are poorly elucidated. We show here that expression of or exposure to the neural cell adhesion molecule (NCAM) strongly affected the motile behaviour of glioma cells independently of homophilic NCAM interactions. Expression of the transmembrane 140 kDa isoform of NCAM (NCAM-140) caused a significant reduction in cellular motility, probably through interference with factors regulating cellular attachment, as NCAM-140-expressing cells exhibited a decreased attachment to a fibronectin substratum compared with NCAM-negative cells. Ectopic expression of the cytoplasmic part of NCAM-140 also inhibited cell motility, presumably via the non-receptor tyrosine kinase p59(fyn) with which NCAM-140 interacts. Furthermore, we showed that the extracellular part of NCAM acted as a paracrine inhibitor of NCAM-negative cell locomotion through a heterophilic interaction with a cell-surface receptor. As we showed that the two N-terminal immunoglobulin modules of NCAM, which are known to bind to heparin, were responsible for this inhibition, we presume that this receptor is a heparan sulfate proteoglycan. A model for the inhibitory effect of NCAM is proposed, which involves competition between NCAM and extracellular components for the binding to membrane-associated heparan sulfate proteoglycan.
Prag
Søren
S
Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Denmark.
Lepekhin
Eugene A
EA
Kolkova
Kateryna
K
Hartmann-Petersen
Rasmus
R
Kawa
Anna
A
Walmod
Peter S
PS
Belman
Vadym
V
Gallagher
Helen C
HC
Berezin
Vladimir
V
Bock
Elisabeth
E
Pedersen
Nina
N
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002448:Cell Adhesion / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005910:Glioma; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D014407:Tumor Cells, Cultured
D016326:Extracellular Matrix Proteins; D019812:Heparan Sulfate Proteoglycans; D016023:Integrins; D019006:Neural Cell Adhesion Molecules; D020033:Protein Isoforms