title: Lrig2 Negatively Regulates Ectodomain Shedding of Axon Guidance Receptors by ADAM Proteases.
abstract: Many guidance receptors are proteolytically cleaved by membrane-associated metalloproteases of the ADAM family, leading to the shedding of their ectodomains. Ectodomain shedding is crucial for receptor signaling and function, but how this process is controlled in neurons remains poorly understood. Here, we show that the transmembrane protein Lrig2 negatively regulates ADAM-mediated guidance receptor proteolysis in neurons. Lrig2 binds Neogenin, a receptor for repulsive guidance molecules (RGMs), and prevents premature Neogenin shedding by ADAM17 (TACE). RGMa reduces Lrig2-Neogenin interactions, providing ADAM17 access to Neogenin and allowing this protease to induce ectodomain shedding. Regulation of ADAM17-mediated Neogenin cleavage by Lrig2 is required for neurite growth inhibition by RGMa in vitro and for cortical neuron migration in vivo. Furthermore, knockdown of Lrig2 significantly improves CNS axon regeneration. Together, our data identify a unique ligand-gated mechanism to control receptor shedding by ADAMs and reveal functions for Lrigs in neuron migration and regenerative failure.
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: van Erp
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
authors.forename: Dianne M A
authors.initials: DMA
authors.lastname: van den Heuvel
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Robinson
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
authors.forename: Anita J C G M
authors.initials: AJCGM
authors.lastname: Hellemons
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
authors.forename: Youri
authors.initials: Y
authors.lastname: Adolfs
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
authors.forename: Eljo Y
authors.initials: EY
authors.lastname: Van Battum
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blokhuis
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Marijn
authors.initials: M
authors.lastname: Kuijpers
authors.affiliation: Proteomics Centre and Department of Cell Biology, Erasmus University Medical Centre, Dr Molewaterplein 50, 3015 GE Rotterdam, the Netherlands.
authors.forename: Jeroen A A
authors.initials: JAA
authors.lastname: Demmers
authors.affiliation: Oncology Research Laboratory, Department of Radiation Sciences, Umeå University, 90187 Umeå, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Hedman
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Siebold
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands. Electronic address: r.j.pasterkamp@umcutrecht.nl.
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D001369:Axons / Q000378:metabolism*; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D003412:Cricetulus; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009420:Nervous System / Q000196:embryology; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012160:Retina / Q000196:embryology; D015398:Signal Transduction
chemical_list: C587593:LRIG2 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C091279:neogenin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse