title: The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition.
abstract: Normal epithelial cells often exert anti-tumour effects against nearby oncogenic cells. In the Drosophila imaginal epithelium, clones of oncogenic cells with loss-of-function mutations in the apico-basal polarity genes scribble or discs large are actively eliminated by cell competition when surrounded by wild-type cells. Although c-Jun N-terminal kinase (JNK) signalling plays a crucial role in this cell elimination, the initial event, which occurs at the interface between normal cells and polarity-deficient cells, has not previously been identified. Here, through a genetic screen in Drosophila, we identify the ligand Sas and the receptor-type tyrosine phosphatase PTP10D as the cell-surface ligand-receptor system that drives tumour-suppressive cell competition. At the interface between the wild-type 'winner' and the polarity-deficient 'loser' clones, winner cells relocalize Sas to the lateral cell surface, whereas loser cells relocalize PTP10D there. This leads to the trans-activation of Sas-PTP10D signalling in loser cells, which restrains EGFR signalling and thereby enables elevated JNK signalling in loser cells, triggering cell elimination. In the absence of Sas-PTP10D, elevated EGFR signalling in loser cells switches the role of JNK from pro-apoptotic to pro-proliferative by inactivating the Hippo pathway, thereby driving the overgrowth of polarity-deficient cells. These findings uncover the mechanism by which normal epithelial cells recognize oncogenic polarity-deficient neighbours to drive cell competition.
authors.affiliation: Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Shizue
authors.initials: S
authors.lastname: Ohsawa
authors.affiliation: Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Kunimasa
authors.affiliation: Laboratory of Genetics, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.|PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Igaki
mesh_terms: D000818:Animals; D017209:Apoptosis; D016764:Cell Polarity; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D008024:Ligands; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; C000621113:Sas protein, Drosophila; C404683:Scrib protein, Drosophila; D025521:Tumor Suppressor Proteins; C070350:dlg1 protein, Drosophila; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; C519388:Ptp10D protein, Drosophila