title: The interaction between cell adhesion molecule L1, matrix metalloproteinase 14, and adenine nucleotide translocator at the plasma membrane regulates L1-mediated neurite outgrowth of murine cerebellar neurons.
abstract: We have identified the adenine nucleotide translocator (ANT) isoforms ANT1 and ANT2 that are present in the plasma membrane of mouse cerebellar neurons as novel binding partners of the cell adhesion molecule L1. The direct interaction between ANT and L1 is mediated by sites within the fibronectin type III domains of L1 and the first and third extracellular loops of the ANT proteins. We also show that L1 interacts with the ANT binding partner matrix metalloprotease 14 (MMP14) and that the ANT proteins bind directly to the L1 interaction partner glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Moreover, we provide evidence that the functional interplay between L1, ANT proteins, MMP14, and GAPDH at the plasma membrane mediates L1-induced neurite outgrowth of cerebellar neurons. Disruption of this interplay by ANT inhibitors, ANT-derived synthetic peptides, and/or function-blocking MMP14 and ANT antibodies leads to alterations in L1-dependent neurite outgrowth. Stimulation of L1-mediated signaling in cerebellar neurons triggers transient ATP secretion via ANT proteins and leads to transient src family-dependent tyrosine phosphorylation of L1, ANT1, ANT2, and MMP14. Thus, our results indicate that plasma membrane-localized ANT1 and ANT2 regulate L1-mediated neurite outgrowth in conjunction with MMP14.
authors.affiliation: Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Loers
authors.forename: Tatjana
authors.initials: T
authors.lastname: Makhina
authors.forename: Ute
authors.initials: U
authors.lastname: Bork
authors.forename: Andrea
authors.initials: A
authors.lastname: Dörner
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Ralf
authors.initials: R
authors.lastname: Kleene
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000378:metabolism*; D033742:Adenine Nucleotide Translocator 2 / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D005260:Female; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D039842:Neural Cell Adhesion Molecule L1 / Q000502:physiology*; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology
chemical_list: D033741:Adenine Nucleotide Translocator 1; D033742:Adenine Nucleotide Translocator 2; D008565:Membrane Proteins; C507096:Mmp14 protein, mouse; D039842:Neural Cell Adhesion Molecule L1; D053511:Matrix Metalloproteinase 14