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Lrig2 Negatively Regulates Ectodomain Shedding of Axon Guidance Receptors by ADAM Proteases.

TitleLrig2 Negatively Regulates Ectodomain Shedding of Axon Guidance Receptors by ADAM Proteases.
Publication TypeJournal Article
Year of Publication2015
Authorsvan Erp S, van den Heuvel DMA, Fujita Y, Robinson RA, Hellemons AJCGM, Adolfs Y, Van Battum EY, Blokhuis AM, Kuijpers M, Demmers JAA, Hedman H, Hoogenraad CC, Siebold C, Yamashita T, R Pasterkamp J
JournalDev Cell
Date Published2015 Dec 07
KeywordsADAM Proteins, ADAM17 Protein, Animals, Axons, Cell Membrane, Cell Movement, CHO Cells, Cricetulus, Gene Expression Regulation, Developmental, HEK293 Cells, Humans, Ligands, Membrane Proteins, Mice, Nervous System, Neurons, Phenotype, Protein Structure, Tertiary, Retina, Signal Transduction

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.

Alternate JournalDev. Cell
PubMed ID26651291
Grant ListC20724/A14414 / / Cancer Research UK / United Kingdom
MR/L017776/1 / / Medical Research Council / United Kingdom
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