TY - JOUR
T1 - The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth
AU - Andersen, Ditte S
AU - Colombani, Julien
AU - Palmerini, Valentina
AU - Chakrabandhu, Krittalak
AU - Boone, Emilie
AU - Röthlisberger, Michael
AU - Toggweiler, Janine
AU - Basler, Konrad
AU - Mapelli, Marina
AU - Hueber, Anne-Odile
AU - Léopold, Pierre
PY - 2015/6/25
Y1 - 2015/6/25
N2 - 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.
AB - 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.
KW - Amino Acid Sequence
KW - Animals
KW - Apoptosis/genetics
KW - Cell Adhesion Molecules/metabolism
KW - Cell Division/genetics
KW - Cell Polarity/genetics
KW - Cell Transformation, Neoplastic/genetics
KW - Disease Models, Animal
KW - Drosophila Proteins/chemistry
KW - Drosophila melanogaster/cytology
KW - Female
KW - Humans
KW - JNK Mitogen-Activated Protein Kinases/metabolism
KW - MAP Kinase Signaling System
KW - Male
KW - Matrix Metalloproteinase 1/metabolism
KW - Membrane Proteins/chemistry
KW - Molecular Sequence Data
KW - Neoplasm Invasiveness/genetics
KW - Neoplasms/enzymology
KW - Receptors, Tumor Necrosis Factor/chemistry
KW - ras Proteins/genetics
U2 - 10.1038/nature14298
DO - 10.1038/nature14298
M3 - Journal article
C2 - 25874673
SN - 0028-0836
VL - 522
SP - 482
EP - 486
JO - Nature
JF - Nature
IS - 7557
ER -