title: Myelin basic protein cleaves cell adhesion molecule L1 and promotes neuritogenesis and cell survival.
abstract: The cell adhesion molecule L1 is a Lewis(x)-carrying glycoprotein that plays important roles in the developing and adult nervous system. Here we show that myelin basic protein (MBP) binds to L1 in a Lewis(x)-dependent manner. Furthermore, we demonstrate that MBP is released by murine cerebellar neurons as a sumoylated dynamin-containing protein upon L1 stimulation and that this MBP cleaves L1 as a serine protease in the L1 extracellular domain at Arg(687) yielding a transmembrane fragment that promotes neurite outgrowth and neuronal survival in cell culture. L1-induced neurite outgrowth and neuronal survival are reduced in MBP-deficient cerebellar neurons and in wild-type cerebellar neurons in the presence of an MBP antibody or L1 peptide containing the MBP cleavage site. Genetic ablation of MBP in shiverer mice and mutagenesis of the proteolytically active site in MBP or of the MBP cleavage site within L1 as well as serine protease inhibitors and an L1 peptide containing the MBP cleavage site abolish generation of the L1 fragment. Our findings provide evidence for novel functions of MBP in the nervous system.
authors.affiliation: From the Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Lutz
authors.forename: Gabriele
authors.initials: G
authors.lastname: Loers
authors.forename: Ralf
authors.initials: R
authors.lastname: Kleene
authors.forename: Iris
authors.initials: I
authors.lastname: Oezen
authors.forename: Hardeep
authors.initials: H
authors.lastname: Kataria
authors.forename: Nainesh
authors.initials: N
authors.lastname: Katagihallimath
authors.forename: Ingke
authors.initials: I
authors.lastname: Braren
authors.forename: George
authors.initials: G
authors.lastname: Harauz
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002470:Cell Survival / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D016296:Mutagenesis; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis
chemical_list: D004676:Myelin Basic Protein; D039842:Neural Cell Adhesion Molecule L1
keywords: Carbohydrate; Carbohydrate-binding Protein; Cell Adhesion; Cell Death; Cell Surface; Myelin; Neurite Outgrowth; Neurobiology; Protease; Protein Processing