title: Polysialic acid controls NCAM signals at cell-cell contacts to regulate focal adhesion independent from FGF receptor activity.
abstract: The polysialic acid (polySia) modification of the neural cell adhesion molecule NCAM is a key regulator of cell migration. Yet its role in NCAM-dependent or NCAM-independent modulation of motility and cell-matrix adhesion is largely unresolved. Here, we demonstrate that loss of polySia attenuates tumour cell migration and augments the number of focal adhesions in a cell-cell contact- and NCAM-dependent manner. In the presence or absence of polySia, NCAM never colocalised with focal adhesions but was enriched at cell-cell contacts. Focal adhesion of polySia- and NCAM-negative cells was enhanced by incubation with soluble NCAM or by removing polySia from heterotypic contacts with polySia-NCAM-positive cells. Focal adhesion was compromised by the src-family kinase inhibitor PP2, whereas loss of polySia or exposure to NCAM promoted the association of p59(Fyn) with the focal adhesion scaffolding protein paxillin. Unlike other NCAM responses, NCAM-induced focal adhesion was not prevented by inhibiting FGF receptor activity and could be evoked by NCAM fragments comprising immunoglobulin domains three and four but not by the NCAM fibronectin domains alone or by an NCAM-derived peptide known to interact with and activate FGF receptors. Together, these data indicate that polySia regulates cell motility through NCAM-induced but FGF-receptor-independent signalling to focal adhesions.
authors.affiliation: Institute of Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
authors.forename: Katinka
authors.initials: K
authors.lastname: Eggers
authors.forename: Sebastian
authors.initials: S
authors.lastname: Werneburg
authors.forename: Andrea
authors.initials: A
authors.lastname: Schertzinger
authors.forename: Markus
authors.initials: M
authors.lastname: Abeln
authors.forename: Miriam
authors.initials: M
authors.lastname: Schiff
authors.forename: Matthias Alexander
authors.initials: MA
authors.lastname: Scharenberg
authors.forename: Hannelore
authors.initials: H
authors.lastname: Burkhardt
authors.forename: Martina
authors.initials: M
authors.lastname: Mühlenhoff
authors.forename: Herbert
authors.initials: H
authors.lastname: Hildebrandt
mesh_terms: D019002:CD56 Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism*; D006026:Glycoside Hydrolases / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051419:Paxillin / Q000378:metabolism; D010590:Phalloidine / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D012794:Sialic Acids / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D019002:CD56 Antigen; D005353:Fibronectins; C522918:NCAM1 protein, human; C496061:PXN protein, human; D051419:Paxillin; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D012794:Sialic Acids; C021319:polysialic acid; D010590:Phalloidine; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006026:Glycoside Hydrolases; C090534:endo-alpha-sialidase