title: Insulin and IGF1 modulate turnover of polysialylated neural cell adhesion molecule (PSA-NCAM) in a process involving specific extracellular matrix components.
abstract: Cellular interactions mediated by the neural cell adhesion molecule (NCAM) are critical in cell migration, differentiation and plasticity. Switching of the NCAM-interaction mode, from adhesion to signalling, is determined by NCAM carrying a particular post-translational modification, polysialic acid (PSA). Regulation of cell-surface PSA-NCAM is traditionally viewed as a direct consequence of polysialyltransferase activity. Taking advantage of the polysialyltransferase Ca²⁺-dependent activity, we demonstrate in TE671 cells that downregulation of PSA-NCAM synthesis constitutes a necessary but not sufficient condition to reduce cell-surface PSA-NCAM; instead, PSA-NCAM turnover required internalization of the molecule into the cytosol. PSA-NCAM internalization was specifically triggered by collagen in the extracellular matrix (ECM) and prevented by insulin-like growth factor (IGF1) and insulin. Our results pose a novel role for IGF1 and insulin in controlling cell migration through modulation of PSA-NCAM turnover at the cell surface. Neural cell adhesion molecules (NCAMs) are critically involved in cell differentiation and migration. Polysialylation (PSA)/desialylation of NCAMs switches their functional interaction mode and, in turn, migration and differentiation. We have found that the desialylation process of PSA-NCAM occurs via endocytosis, induced by collagen-IV and blocked by insulin-like growth factor (IGF1) and insulin, suggesting a novel association between PSA-NCAM, IGF1/insulin and brain/tumour plasticity.
authors.affiliation: Faculty of Medical and Health Sciences, Centre for Brain Research, The University of Auckland, Auckland, New Zealand.
authors.forename: Hector J
authors.initials: HJ
authors.lastname: Monzo
authors.forename: Thomas I H
authors.initials: TI
authors.lastname: Park
authors.forename: Birger V
authors.initials: BV
authors.lastname: Dieriks
authors.forename: Deidre
authors.initials: D
authors.lastname: Jansson
authors.forename: Richard L M
authors.initials: RL
authors.lastname: Faull
authors.forename: Mike
authors.initials: M
authors.lastname: Dragunow
authors.forename: Maurice A
authors.initials: MA
authors.lastname: Curtis
mesh_terms: D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D024141:Collagen Type IV / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D060888:Real-Time Polymerase Chain Reaction; D012794:Sialic Acids / Q000378:metabolism*
chemical_list: D024141:Collagen Type IV; D007004:Hypoglycemic Agents; D007328:Insulin; D019006:Neural Cell Adhesion Molecules; D012794:Sialic Acids; C021319:polysialic acid; D007334:Insulin-Like Growth Factor I; D002118:Calcium
keywords: IGF1; PSA-NCAM; extracellular matrix; insulin; migration