The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth

Cell polarity is an important feature of many tissues and is often disrupted in cancer; the TNF receptor Grindelwald is now shown to have an important role in coordinating cell polarity and neoplastic growth in a Drosophila model. Linking cell polarity and neoplasia Cell polarity is an important fea...

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Published in:	Nature (London) Vol. 522; no. 7557; pp. 482 - 486
Main Authors:	Andersen, Ditte S., Colombani, Julien, Palmerini, Valentina, Chakrabandhu, Krittalak, Boone, Emilie, Röthlisberger, Michael, Toggweiler, Janine, Basler, Konrad, Mapelli, Marina, Hueber, Anne-Odile, Léopold, Pierre
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 25.06.2015 Nature Publishing Group
Subjects:	631/80/304 Amino Acid Sequence Animals Apoptosis Apoptosis - genetics Biochemistry, Molecular Biology Cancer Cell Adhesion Molecules Cell Adhesion Molecules - metabolism Cell Division Cell Division - genetics Cell Polarity Cell Polarity - genetics Cell Transformation, Neoplastic Cell Transformation, Neoplastic - genetics Cloning Development Biology Disease Models, Animal Drosophila melanogaster Drosophila melanogaster - cytology Drosophila melanogaster - enzymology Drosophila melanogaster - genetics Drosophila melanogaster - metabolism Drosophila Proteins Drosophila Proteins - chemistry Drosophila Proteins - deficiency Drosophila Proteins - genetics Drosophila Proteins - metabolism Female Genes Genomics Genotype & phenotype Humanities and Social Sciences Humans Insects JNK Mitogen-Activated Protein Kinases JNK Mitogen-Activated Protein Kinases - metabolism letter Life Sciences Male MAP Kinase Signaling System Matrix Metalloproteinase 1 Matrix Metalloproteinase 1 - metabolism Membrane Proteins Membrane Proteins - chemistry Membrane Proteins - deficiency Membrane Proteins - genetics Membrane Proteins - metabolism Molecular Sequence Data multidisciplinary Neoplasm Invasiveness Neoplasm Invasiveness - genetics Neoplasms Neoplasms - enzymology Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology Proteins ras Proteins ras Proteins - genetics ras Proteins - metabolism Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor - chemistry Receptors, Tumor Necrosis Factor - genetics Receptors, Tumor Necrosis Factor - metabolism Science Tumors
ISSN:	0028-0836, 1476-4687, 1476-4687
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Summary:	Cell polarity is an important feature of many tissues and is often disrupted in cancer; the TNF receptor Grindelwald is now shown to have an important role in coordinating cell polarity and neoplastic growth in a Drosophila model. Linking cell polarity and neoplasia Cell polarity is an important feature of many tissues, and is often disrupted in cancer. This study demonstrates, in a Drosophila model, that the tumour necrosis factor receptor molecule Grindelwald plays an important role in coordinating cell polarity and neoplastic growth. The authors identify Grindelwald as the long-sought receptor for the apoptosis-inducing factor Eiger, and show that Grindelwald functions by integrating signals from Eiger as well as from cell polarity cues. Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth 1 , we identified grindelwald ( grnd ), a gene encoding a transmembrane protein with homology to members of the tumour necrosis factor receptor (TNFR) superfamily. Here we show that Grnd mediates the pro-apoptotic functions of Eiger (Egr), the unique Drosophila TNF, and that overexpression of an active form of Grnd lacking the extracellular domain is sufficient to activate JNK signalling in vivo . Grnd also promotes the invasiveness of Ras V12 /scrib −/− tumours through Egr-dependent Matrix metalloprotease-1 (Mmp1) expression. Grnd localizes to the subapical membrane domain with the cell polarity determinant Crumbs (Crb) and couples Crb-induced loss of polarity with JNK activation and neoplastic growth through physical interaction with Veli (also known as Lin-7). Therefore, Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/nature14298