title: Heparan sulfate proteoglycan syndecan-3 is a novel receptor for GDNF, neurturin, and artemin.
abstract: Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson's disease. Soluble GFLs bind to a ligand-specific glycosylphosphatidylinositol-anchored coreceptor (GDNF family receptor α) and signal through the receptor tyrosine kinase RET. In this paper, we show that all immobilized matrix-bound GFLs, except persephin, use a fundamentally different receptor. They interact with syndecan-3, a transmembrane heparan sulfate (HS) proteoglycan, by binding to its HS chains with high affinity. GFL-syndecan-3 interaction mediates both cell spreading and neurite outgrowth with the involvement of Src kinase activation. GDNF promotes migration of cortical neurons in a syndecan-3-dependent manner, and in agreement, mice lacking syndecan-3 or GDNF have a reduced number of cortical γ-aminobutyric acid-releasing neurons, suggesting a central role for the two molecules in cortical development. Collectively, syndecan-3 may directly transduce GFL signals or serve as a coreceptor, presenting GFLs to the signaling receptor RET.
authors.affiliation: Institute of Biotechnology, Viikki Biocenter, and 2 Neuroscience Center, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Maxim M
authors.initials: MM
authors.lastname: Bespalov
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Sidorova
authors.forename: Sarka
authors.initials: S
authors.lastname: Tumova
authors.forename: Anni
authors.initials: A
authors.lastname: Ahonen-Bishopp
authors.forename: Ana Cathia
authors.initials: AC
authors.lastname: Magalhães
authors.forename: Evgeny
authors.initials: E
authors.lastname: Kulesskiy
authors.forename: Mikhail
authors.initials: M
authors.lastname: Paveliev
authors.forename: Claudio
authors.initials: C
authors.lastname: Rivera
authors.forename: Heikki
authors.initials: H
authors.lastname: Rauvala
authors.forename: Mart
authors.initials: M
authors.lastname: Saarma
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D006493:Heparin / Q000378:metabolism; D006801:Humans; D055767:Immobilized Proteins / Q000378:metabolism; D007395:Interneurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D051101:Neurturin / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D053670:Syndecan-3 / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D055767:Immobilized Proteins; D008024:Ligands; D009419:Nerve Tissue Proteins; D051101:Neurturin; D053670:Syndecan-3; D006493:Heparin; D019061:src-Family Kinases