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.
| Original language | English |
|---|---|
| Pages (from-to) | 482-486 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 522 |
| Issue number | 7557 |
| DOIs | |
| Publication status | Published - Jun 25 2015 |
Fingerprint
ASJC Scopus subject areas
- General
- Medicine(all)
Cite this
The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. / Andersen, Ditte S.; Colombani, Julien; Palmerini, Valentina; Chakrabandhu, Krittalak; Boone, Emilie; Röthlisberger, Michael; Toggweiler, Janine; Basler, Konrad; Mapelli, Marina; Hueber, Anne Odile; Léopold, Pierre.
In: Nature, Vol. 522, No. 7557, 25.06.2015, p. 482-486.Research output: Contribution to journal › Article
}
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.
UR - http://www.scopus.com/inward/record.url?scp=84933054764&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84933054764&partnerID=8YFLogxK
U2 - 10.1038/nature14298
DO - 10.1038/nature14298
M3 - Article
C2 - 25874673
AN - SCOPUS:84933054764
VL - 522
SP - 482
EP - 486
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7557
ER -