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Titel: Novel Proteolytic Fragments of the Cell Adhesion Molecule L1, Their Intracellular Trafficking and Functional Roles in the Nervous Systemof Mus Musculus (Linnaeus, 1758)
Sonstige Titel: Neue proteolytische Fragmente des Zelladhäsionsmoleküls L1, ihr intrazellulärer Transport und funktionelle Rollen im Nervensystem von Mus Musculus (Linneaus, 1758)
Sprache: Englisch
Autor/Autorin: Lutz, David
Schlagwörter: L1; Import; Proteolyse; L1; import; proteolysis
Erscheinungsdatum: 2013
Tag der mündlichen Prüfung: 2013-04-26
Zusammenfassung: 
Homophilic interactions of the cell adhesion molecule L1 mediate not only mechanical adhesion among cells, but also, importantly, propagate intracellular signals due to connections with the major signalling networks that control most cellular responses. The ability of the cell adhesion molecule L1 to modulate cellular responses has been traditionally viewed as a direct consequence of its adhesive functions. However, after L1-specific stimulation with antibody 557, shedding of L1 occurs and dispossesses this recognition molecule of its adhesiveness as a static cell surface molecule. In fact, under these conditions stimulation of signalling cascades becomes a manifestation of emerging soluble L1 proteolytic fragments, which act as triggers of gene expression. The present work provides novel insights into the proteolytic processing of L1 upon L1-antibody stimulation: triggering of signalling with L1-antibody 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 of L1. This fragment travels from the plasma membrane to the late endosomal compartment, where it is released from endosomal membranes into the cytoplasm, and then transported into the nucleus by a pathway that depends on importin and chromatin-modifying protein 1. The 70 kDa L1 fragment is not only transported to the endosomal compartment, but also shortly after generation cleaved by cathepsin E at the plasma membrane. Cathepsin E cleaves the 70 kDa L1 fragment at Glu1167 generating a smaller 30 kDa fragment. This 30 kDa L1 fragment is rapidly released into the cytoplasma after generation at the plasma membrane and is then translocated into the nucleus in an importin-dependent manner. Addition of the serine protease inhibitor aprotinin or mutation of the sumoylation site at Lys1172 abolishes L1-stimulated generation and nuclear import of both fragments. Their nuclear import is also impaired after alteration of the nuclear localization signal at Lys1147 of L1. Mutation of the putative cleavage site at Glu1167 as well as addition of the aspartyl protease inhibitor pepstatin abolishes generation of the 30 kDa L1 fragment. Furthermore, pepstatin inhibits L1-dependent migration of cerebellar neurons from explants, but not neurite outgrowth, indicating that the cathepsin E-mediated cleavage and/or possibly nuclear import of the 30 kDa fragment are necessary for L1-induced neuronal migration. Since aprotinin inhibits L1-stimulated neurite outgrowth, it is very likely that the 70 kDa fragment is involved in regulation of neuritogenesis. Nuclear import of the 70 kDa fragment might activate cellular responses in parallel or in association with phosphorylation-dependent signalling 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’s disease suggest that this fragment is functionally implicated in development, regeneration, neurodegeneration, and possibly sysnaptic plasticity in the mature nervous system.
URI: https://ediss.sub.uni-hamburg.de/handle/ediss/4919
URN: urn:nbn:de:gbv:18-61854
Dokumenttyp: Dissertation
Hauptberichter: Schachner, Melitta (Prof. Dr.)
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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