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

Ditte S. Andersen, Julien Colombani, Valentina Palmerini, Krittalak Chakrabandhu, Emilie Boone, Michael Röthlisberger, Janine Toggweiler, Konrad Basler, Marina Mapelli, Anne Odile Hueber, Pierre Léopold

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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 languageEnglish
Pages (from-to)482-486
Number of pages5
JournalNature
Volume522
Issue number7557
DOIs
Publication statusPublished - Jun 25 2015

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ASJC Scopus subject areas

  • General
  • Medicine(all)

Cite this

Andersen, D. S., Colombani, J., Palmerini, V., Chakrabandhu, K., Boone, E., Röthlisberger, M., Toggweiler, J., Basler, K., Mapelli, M., Hueber, A. O., & Léopold, P. (2015). The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature, 522(7557), 482-486. https://doi.org/10.1038/nature14298