Article abstract
Nature Medicine 13, 1070 - 1077 (2007)
Published online: 2 September 2007 | doi:10.1038/nm1627
Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL
Klaus W Wagner1,7,8, Elizabeth A Punnoose1,2,8, Thomas Januario1, David A Lawrence2, Robert M Pitti2, Kate Lancaster3, Dori Lee1, Melissa von Goetz1, Sharon Fong Yee4, Klara Totpal4, Ling Huw1, Viswanatham Katta3, Guy Cavet5, Sarah G Hymowitz6, Lukas Amler1 & Avi Ashkenazi2
Abstract
Apo2L/TRAIL stimulates cancer cell death through the proapoptotic receptors DR4 and DR5, but the determinants of tumor susceptibility to this ligand are not fully defined. mRNA expression of the peptidyl O-glycosyltransferase GALNT14 correlated with Apo2L/TRAIL sensitivity in pancreatic carcinoma, non–small-cell lung carcinoma and melanoma cell lines, and up to 30% of samples from various human malignancies showed GALNT14 overexpression. RNA interference of GALNT14 reduced cellular Apo2L/TRAIL sensitivity, whereas overexpression increased responsiveness. Biochemical analysis of DR5 identified several ectodomain O-(N-acetyl galactosamine–galactose–sialic acid) structures. Sequence comparison predicted conserved extracellular DR4 and DR5 O-glycosylation sites; progressive mutation of the DR5 sites attenuated apoptotic signaling. O-glycosylation promoted ligand-stimulated clustering of DR4 and DR5, which mediated recruitment and activation of the apoptosis-initiating protease caspase-8. These results uncover a new link between death-receptor O-glycosylation and apoptotic signaling, providing potential predictive biomarkers for Apo2L/TRAIL-based cancer therapy.
- Department of Molecular Diagnostics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
- Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
- Department of Analytical Development, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
- Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
- Department of Bioinformatics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
- Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
- Present address: Indiana University School of Medicine, 1001 West 10th Street, Indianapolis, Indiana 46202, USA.
- These authors contributed equally to this work.
Correspondence to: Avi Ashkenazi2 e-mail: aa@gene.com
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