Molekulare Analyse CD95-mediierter Signalwege im Nervensystem
Final Report Abstract
Apoptosis or programmed cell-death is an important process involved in tissue homeostasis, development and a variety of immune responses. The apoptotic program can be activated via transmembrane receptors stimulated with their cognate ligands. The presence of a wellconserved region of 80 aminoacids in their intracellular tail, the Death-Domain (DD), has conferred those receptors the general name of "death receptors", which includes the TNF receptor-I (TNFRI), TRAMP, DR3/APO-3, TRAIL-receptor 1 (TRAIL-RI/DR4), TRAIL-receptor 2 (TRAIL-R1/DR5), DR6 and CD95 (Fas/Apo-1). The pro-apoptotic properties of the CD95 system have been extensively studied during the past decades. Nevertheless, CD95 has now emerged as an important activator of other major signaling pathways. Stimulation of CD95 has been described to activate the MAPK pathways p38, JNK and ERK and the transcription factor NFkB. Thereby, CD95 has been shown to be particularly involved in tumor cell invasion, neurite sprouting and outgrowth, as well as cell proliferation - functions that lay to rest the general assumption, of CD95 as a death receptor. In our group we have recently described a novel molecular link between CD95 and the phosphatydilinositol-3-kinase (PI3K) pathway. Stimulation of CD95 on glioblastoma cells leads to activation of the src-family-kinase yes, which in turn phosphorylates CD95 to enable recmitment of the p85 subunit of PI3K. Activated PI3K triggers further activation of AKT and MMPs leading to increased invasion of tumour cells.
Publications
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(2008) Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell, 13, 235-248
Kleber S, Sancho-Martinez I, Wiestler B, Beisel A, Gieffers C, Hill O, Thiemann M, Mueller W, Sykora J, Kuhn A, Schreglmann N, Letellier E, Zuliani C, Klussmann S, Teodorczyk M, Grone HJ, Ganten TM, Sultmann H, Tuttenberg J, von DA, Regnier-Vigouroux A, Herold-Mende C, and Martin-Villalba A
