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Unravelling the molecular players of the CD95 non-canonical pathway

The CD95 canonical pathway leading to apoptosis has been subject of extensive studies in the past decades. In our lab we have unravelled a novel non-canonical pathway downstream of CD95. Triggering of CD95 in different cellular systems leads to activation of phosphatidylinositol 3-kinase (PI3K) and increased migration and/or differentiation depending on the system of study. Binding of CD95Ligand to CD95 recruits a newly described set of proteins to CD95.
In glioma, Neural Stem Cells (NSCs) and immune cells, non-receptor tyrosine kinases from the Src family Kinase (SFKs) are activated in order to transduce the signals emanating from CD95. Activation of SFKs leads to increased PI3K activity upon CD95 stimulation. The YXXL motif present in the Death Domain of CD95 might potentially serve as a docking site for this variety of SH2-domain containing proteins.
c-Src, a non-receptor tyrosine kinase belonging to the Src family kinases (SFKs), was found to co-precipitate with CD95 and PI3K, thus, being part of the so called PI3K-Activation-Complex (PAC) in NSCs. Importantly, c-Src knockdown completely abolished PI3K activation upon CD95 stimulation also abolishing CD95-induced differentiation. In Glioblastoma Multiforme (GBM) we identified Yes as the SFK recruited to the CD95 PAC. PI3K activation in GBM cells leads to increased migration upon CD95 stimulation.
We are currently examining the role of the PI3K downstream target mTOR and the contribution of protein translation to CD95/PI3K signaling. In addition, we have observed that the CD95 non-canonical pathway leads to different phenotypes depending on the cellular context. Thus, CD95 is able to transduce its signal by formation of different protein complexes depending on the cellular context. Identification of the different molecular complexes in the different cellular systems and their relation to tumor formation are subject of current studies.

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