title: Generation and nuclear translocation of sumoylated transmembrane fragment of cell adhesion molecule L1.
abstract: The functions of the cell adhesion molecule L1 in the developing and adult nervous system are triggered by homophilic and heterophilic interactions that stimulate signal transductions that activate cellular responses. Here, we show that stimulation of signaling by function-triggering L1 antibodies or L1-Fc leads to serine protease-dependent cleavage of full-length L1 at the plasma membrane and generation of a sumoylated transmembrane 70-kDa fragment comprising the intracellular and transmembrane domains and part of the extracellular domain. The 70-kDa transmembrane fragment is transported from the plasma membrane to a late endosomal compartment, released from endosomal membranes into the cytoplasm, and transferred from there into the nucleus by a pathway that depends on importin and chromatin-modifying protein 1. Mutation of the sumoylation site at Lys(1172) or of the nuclear localization signal at Lys(1147) abolished L1-stimulated generation or nuclear import of the 70-kDa fragment, respectively. Nuclear import of the 70-kDa fragment may activate cellular responses in parallel or in association with phosphorylation-dependent signaling pathways. Alterations in the levels of the 70-kDa fragment during development and in the adult after spinal cord injury or in a mouse model of Alzheimer disease suggest that this fragment is functionally implicated in development, regeneration, neurodegeneration, tumorigenesis, and possibly synaptic plasticity in the mature nervous system.
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Lutz
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Wolters-Eisfeld
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Gunjan
authors.initials: G
authors.lastname: Joshi
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Nevena
authors.initials: N
authors.lastname: Djogo
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Jakovcevski
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany; Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854; Center for Neuroscience, Shantou University Medical College, 22 Xin Ling Road, Shantou 515041, China. Electronic address: schachner@stu.edu.cn.
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kleene
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013116:Spinal Cord / Q000196:embryology / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation
chemical_list: D009419:Nerve Tissue Proteins; D039842:Neural Cell Adhesion Molecule L1; D019913:Nuclear Localization Signals