Polysialic acid directs tumor cell growth by controlling heterophilic neural cell adhesion molecule interactions.
Polysialic acid (PSA), a carbohydrate polymer attached to the neural cell adhesion molecule (NCAM), promotes neural plasticity and tumor malignancy, but its mode of action is controversial. Here we establish that PSA controls tumor cell growth and differentiation by interfering with NCAM signaling at cell-cell contacts. Interactions between cells with different PSA and NCAM expression profiles were initiated by enzymatic removal of PSA and by ectopic expression of NCAM or PSA-NCAM. Removal of PSA from the cell surface led to reduced proliferation and activated extracellular signal-regulated kinase (ERK), inducing enhanced survival and neuronal differentiation of neuroblastoma cells. Blocking with an NCAM-specific peptide prevented these effects. Combinatorial transinteraction studies with cells and membranes with different PSA and NCAM phenotypes revealed that heterophilic NCAM binding mimics the cellular responses to PSA removal. In conclusion, our data demonstrate that PSA masks heterophilic NCAM signals, having a direct impact on tumor cell growth. This provides a mechanism for how PSA may promote the genesis and progression of highly aggressive PSA-NCAM-positive tumors.
Seidenfaden
Ralph
R
Institut für Zoologie (220), Universität Hohenheim, 70593 Stuttgart, Germany.
Krauter
Andrea
A
Schertzinger
Frank
F
Gerardy-Schahn
Rita
R
Hildebrandt
Herbert
H
D017209:Apoptosis; D002448:Cell Adhesion; D002454:Cell Differentiation; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D010641:Phenotype; D010766:Phosphorylation; D011108:Polymers / Q000737:chemistry; D011485:Protein Binding; D012794:Sialic Acids / Q000494:pharmacology*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D019006:Neural Cell Adhesion Molecules; D011108:Polymers; D012794:Sialic Acids; C021319:polysialic acid; D020928:Mitogen-Activated Protein Kinases