title: The protein-tyrosine phosphatase DEP-1 promotes migration and phagocytic activity of microglial cells in part through negative regulation of fyn tyrosine kinase.
abstract: Microglia cells are brain macrophages whose proper functioning is essential for maintenance and repair processes of the central nervous system (CNS). Migration and phagocytosis are critical aspects of microglial activity. By using genetically modified cell lines and knockout mice we demonstrate here that the receptor protein-tyrosine phosphatase (PTP) DEP-1 (also known as PTPRJ or CD148) acts as a positive regulator of both processes in vitro and in vivo. Notably, reduced microglial migration was detectable in brains of Ptprj-/-mice using a wounding assay. Mechanistically, density-enhanced phosphatase-1 (DEP-1) may in part function by inhibiting the activity of the Src family kinase Fyn. In the microglial cell line BV2 DEP-1 depletion by shRNA-mediated knockdown resulted in enhanced phosphorylation of the Fyn activating tyrosine (Tyr420) and elevated specific Fyn-kinase activity in immunoprecipitates. Moreover, Fyn mRNA and protein levels were reduced in DEP-1 deficient microglia cells. Consistent with a negative regulatory role of Fyn for microglial functions, which is inhibited by DEP-1, microglial cells from Fyn-/-mice exhibited elevated migration and phagocytosis. Enhanced microglia migration to a site of injury was also observed in Fyn-/-mice in vivo. Taken together our data revealed a previously unrecognized role of DEP-1 and suggest the existence of a potential DEP-1-Fyn axis in the regulation of microglial functions. GLIA 2017;65:416-428.
authors.affiliation: Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knöll-Straße 2, Jena, Germany.|Leibniz Institute on Aging, Beutenberstraße 11, Jena, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Schneble
authors.affiliation: Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knöll-Straße 2, Jena, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Müller
authors.affiliation: Institute for Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke-University, Leipziger Str. 44, Magdeburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kliche
authors.affiliation: Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knöll-Straße 2, Jena, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bauer
authors.affiliation: Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knöll-Straße 2, Jena, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wetzker
authors.affiliation: Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knöll-Straße 2, Jena, Germany.
authors.forename: Frank-D
authors.initials: FD
authors.lastname: Böhmer
authors.affiliation: Leibniz Institute on Aging, Beutenberstraße 11, Jena, Germany.
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
authors.affiliation: Institute of Molecular Cell Biology, Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knöll-Straße 2, Jena, Germany.
authors.forename: Jörg P
authors.initials: JP
authors.lastname: Müller
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics*; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D010587:Phagocytosis / Q000235:genetics* / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D051076:Proto-Oncogene Proteins c-fyn; C098066:Ptprj protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3
keywords: activation; microglia; negative regulator; phagocytosis; phosphorylation