title: Yes and PI3K bind CD95 to signal invasion of glioblastoma.
abstract: Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo.
authors.affiliation: Molecular Neurobiology Group, German Cancer Research Center (DKFZ), INF 581, 69120 Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kleber
authors.forename: Ignacio
authors.initials: I
authors.lastname: Sancho-Martinez
authors.forename: Benedict
authors.initials: B
authors.lastname: Wiestler
authors.forename: Alexandra
authors.initials: A
authors.lastname: Beisel
authors.forename: Christian
authors.initials: C
authors.lastname: Gieffers
authors.forename: Oliver
authors.initials: O
authors.lastname: Hill
authors.forename: Meinolf
authors.initials: M
authors.lastname: Thiemann
authors.forename: Wolf
authors.initials: W
authors.lastname: Mueller
authors.forename: Jaromir
authors.initials: J
authors.lastname: Sykora
authors.forename: Andreas
authors.initials: A
authors.lastname: Kuhn
authors.forename: Nina
authors.initials: N
authors.lastname: Schreglmann
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Letellier
authors.forename: Cecilia
authors.initials: C
authors.lastname: Zuliani
authors.forename: Stefan
authors.initials: S
authors.lastname: Klussmann
authors.forename: Marcin
authors.initials: M
authors.lastname: Teodorczyk
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Tom M
authors.initials: TM
authors.lastname: Ganten
authors.forename: Holger
authors.initials: H
authors.lastname: Sültmann
authors.forename: Jochen
authors.initials: J
authors.lastname: Tüttenberg
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Anne
authors.initials: A
authors.lastname: Regnier-Vigouroux
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Ana
authors.initials: A
authors.lastname: Martin-Villalba
mesh_terms: D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism*; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051575:Proto-Oncogene Proteins c-yes / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014185:Transplantation, Isogeneic; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; D053222:Fas Ligand Protein; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D019869:Phosphatidylinositol 3-Kinases; D051575:Proto-Oncogene Proteins c-yes; C489834:YES1 protein, human; C496639:Yes1 protein, mouse; D019061:src-Family Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D020782:Matrix Metalloproteinases