title: The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth.
abstract: 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, 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.
authors: 1] University of Nice-Sophia Antipolis, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [2] CNRS, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [3] INSERM, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [4] Genetics and Physiology of Growth laboratory, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France.
authors: Ditte S
authors: DS
authors: Andersen
authors: 1] University of Nice-Sophia Antipolis, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [2] CNRS, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [3] INSERM, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [4] Genetics and Physiology of Growth laboratory, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France.
authors: Julien
authors: J
authors: Colombani
authors: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors: Valentina
authors: V
authors: Palmerini
authors: 1] University of Nice-Sophia Antipolis, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [2] CNRS, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [3] INSERM, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [4] Death receptors Signalling and Cancer Therapy laboratory, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France.
authors: Krittalak
authors: K
authors: Chakrabandhu
authors: 1] University of Nice-Sophia Antipolis, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [2] CNRS, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [3] INSERM, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [4] Genetics and Physiology of Growth laboratory, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France.
authors: Emilie
authors: E
authors: Boone
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors: Michael
authors: M
authors: Röthlisberger
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors: Janine
authors: J
authors: Toggweiler
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors: Konrad
authors: K
authors: Basler
authors: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
authors: Marina
authors: M
authors: Mapelli
authors: 1] University of Nice-Sophia Antipolis, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [2] CNRS, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [3] INSERM, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [4] Death receptors Signalling and Cancer Therapy laboratory, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France.
authors: Anne-Odile
authors: AO
authors: Hueber
authors: 1] University of Nice-Sophia Antipolis, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [2] CNRS, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [3] INSERM, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France [4] Genetics and Physiology of Growth laboratory, Institute of Biology Valrose, Parc Valrose, 06108 Nice, France.
authors: Pierre
authors: P
authors: Léopold
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D029721:Drosophila Proteins; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; C404683:Scrib protein, Drosophila; C494546:Veli protein, Drosophila; C064360:crb protein, Drosophila; C464573:egr protein, Drosophila; C000599674:grnd protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1; D018631:ras Proteins