Ligand stimulation of CD95 induces activation of PIk3 followed by phosphorylation of caspase-8  

作　　者：Christina Helmke Monika Raab Franz Rodel Yves Matthess Thomas Oellerich Ranadip Mandal Mourad Sanhaji Henning Urlaub Claus Rodel Sven Becker Klaus Strebhardt 

机构地区：[1]Department of Gynecology, Goethe University, 60590 Frankfurt, Germany [2]Department of Radiotherapy and Oncology, Goethe University, 60590 Frankfurt, Germany [3]German Cancer Consortium (DKTK)/German Cancer Research Center, 69120 Heidelberg, Germany [4]Department of Medicine II, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany [5]Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 3 7077 Gottingen, Germany [6]Bioanalytics, Institute for Clinical Chemistry, University Medical Center Gottingen, Robert-Koch-Straβe 40, 37075 Gottingen, Germany

出　　处：《Cell Research》2016年第8期914-934,共21页细胞研究（英文版）

摘　　要：Upon interaction of the CD95 receptor with its ligand, sequential association of the adaptor molecule FADD （MORT1）, pro-forms of caspases-8/10, and the caspase-8/10 regulator c-FLIP leads to the formation of a death-inducing signaling complex. Here, we identify polo-like kinase （Pik） 3 as a new interaction partner of the death receptor CD95. The enzymatic activity of Plk3 increases following interaction of the CD95 receptor with its ligand. Knockout （KO） or knockdown of caspase-8, CD95 or FADD prevents activation of Plk3 upon CD95 stimulation, suggesting a requirement of a functional DISC for Plk3 activation. Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function. Stimulation of CD95 in cells expressing a non-phosphorylatable caspase-8-T273A mutant in a rescue experiment or in PIk3-KO cells generated by CRISPR/Cas9 reduces the processing of caspase-8 prominently. Low T273 phosphorylation correlates significantly with low Plk3 expression in a cohort of 95 anal tumor patients. Our data suggest a novel mechanism of kinase activation within the Plk family and propose a new model for the stimulation of the extrinsic death pathway in tumors with high Plk3 expression.

关 键 词：polo-like kinase CASPASE-8 CD95/Fas receptor apoptosis kinase regulation 

分 类 号：Q945.61[生物学—植物学] Q51