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

VL - 522

SP - 482

EP - 486

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7557

ER -