Yes and PI3K bind CD95 to signal invasion of glioblastoma.
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.
Kleber
Susanne
S
Molecular Neurobiology Group, German Cancer Research Center (DKFZ), INF 581, 69120 Heidelberg, Germany.
Sancho-Martinez
Ignacio
I
Wiestler
Benedict
B
Beisel
Alexandra
A
Gieffers
Christian
C
Hill
Oliver
O
Thiemann
Meinolf
M
Mueller
Wolf
W
Sykora
Jaromir
J
Kuhn
Andreas
A
Schreglmann
Nina
N
Letellier
Elisabeth
E
Zuliani
Cecilia
C
Klussmann
Stefan
S
Teodorczyk
Marcin
M
Gröne
Hermann-Josef
HJ
Ganten
Tom M
TM
Sültmann
Holger
H
Tüttenberg
Jochen
J
von Deimling
Andreas
A
Regnier-Vigouroux
Anne
A
Herold-Mende
Christel
C
Martin-Villalba
Ana
A
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
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