title: Morphoregulation by acetylcholinesterase in fibroblasts and astrocytes.
abstract: Acetylcholinesterase (AChE) terminates neurotransmission at cholinergic synapses by hydrolysing acetylcholine, but also has non-enzymatic morphoregulatory effects on neurons such as stimulation of neurite outgrowth. It is widely expressed outside the nervous system, but its function in non-neuronal cells is unclear. Here we have investigated the distribution and function of AChE in fibroblasts and astrocytes. We show that these cells express high levels of AChE protein that co-migrates with recombinant AChE but contains little catalytic activity. Fibroblasts express transcripts encoding the synaptic AChE-T isoform and its membrane anchoring peptide PRiMA-I. AChE is strikingly distributed in arcs, rings and patches at the leading edge of spreading and migrating fibroblasts and astrocytes, close to the cell-substratum interface, and in neuronal growth cones. During in vivo healing of mouse skin, AChE becomes highly expressed in re-epithelialising epidermal keratinocytes 1 day after wounding. AChE appears to be functionally important for polarised cell migration, since an AChE antibody reduces substratum adhesion of fibroblasts, and slows wound healing in vitro as effectively as a beta1-integrin antibody. Moreover, elevation of AChE expression increases fibroblast wound healing independently of catalytic activity. Interestingly, AChE surface patches precisely co-localise with amyloid precursor protein and the extracellular matrix protein perlecan, but not focal adhesions or alpha-dystroglycan, and contain a high concentration of tyrosine phosphorylated proteins in spreading cells. These findings suggest that cell surface AChE, possibly in a novel signalling complex containing APP and perlecan, contributes to a generalised mechanism for polarised membrane protrusion and migration in all adherent cells.
authors.affiliation: Division of Cell & Molecular Biology, Faculty of Natural Sciences, Imperial College London, South Kensington Campus, London, UK.
authors.forename: Alexandra A
authors.initials: AA
authors.lastname: Anderson
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Ushakov
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ferenczi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Mori
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.forename: Jane L
authors.initials: JL
authors.lastname: Saffell
mesh_terms: D000110:Acetylcholinesterase / Q000276:immunology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D002384:Catalysis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049030:Dystroglycans / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D022001:Focal Adhesions / Q000187:drug effects / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010455:Peptides / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011554:Pseudopodia / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity / Q000187:drug effects; D016596:Vinculin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D019812:Heparan Sulfate Proteoglycans; D019012:Integrin beta1; D010455:Peptides; D012333:RNA, Messenger; D016596:Vinculin; C071927:perlecan; D049030:Dystroglycans; D019000:Phosphotyrosine; D000110:Acetylcholinesterase