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: Susanne Kleber, Ignacio Sancho-Martinez, Benedict Wiestler, Alexandra Beisel, Christian Gieffers, Oliver Hill, Meinolf Thiemann, Wolf Mueller, Jaromir Sykora, Andreas Kuhn, Nina Schreglmann, Elisabeth Letellier, Cecilia Zuliani, Stefan Klussmann, Marcin Teodorczyk, Hermann-Josef Gröne, Tom M Ganten, Holger Sültmann, Jochen Tüttenberg, Andreas von Deimling, Anne Regnier-Vigouroux, Christel Herold-Mende, Ana Martin-Villalba
• Journal: Cancer cell (Cancer Cell) Vol. 13 Issue 3 Pg. 235-48 (Mar 2008) ISSN: 1878-3686 [Electronic] United States
• PMID: 18328427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Death Domain Receptor Signaling Adaptor Proteins
• Fas Ligand Protein
• RNA, Small Interfering
• Recombinant Fusion Proteins
• fas Receptor
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-yes
• YES1 protein, human
• Yes1 protein, mouse
• src-Family Kinases
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3
• Matrix Metalloproteinases

Topics

• Animals
• Apoptosis
• Brain Neoplasms (enzymology, genetics, immunology, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement
• Death Domain Receptor Signaling Adaptor Proteins (metabolism)
• Fas Ligand Protein (metabolism)
• Glioblastoma (enzymology, genetics, immunology, metabolism, pathology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Matrix Metalloproteinases (genetics, metabolism)
• Mice
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-yes (genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Recombinant Fusion Proteins (metabolism)
• Signal Transduction
• Transfection
• Transplantation, Isogeneic
• Tumor Cells, Cultured
• fas Receptor (metabolism)
• src-Family Kinases (metabolism)