title: EGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth.
abstract: Multiple signalling events interact in cancer cells. Oncogenic Ras cooperates with Egfr, which cannot be explained by the canonical signalling paradigm. In turn, Egfr cooperates with Hedgehog signalling. How oncogenic Ras elicits and integrates Egfr and Hedgehog signals to drive overgrowth remains unclear. Using a Drosophila tumour model, we show that Egfr cooperates with oncogenic Ras via Arf6, which functions as a novel regulator of Hh signalling. Oncogenic Ras induces the expression of Egfr ligands. Egfr then signals through Arf6, which regulates Hh transport to promote Hh signalling. Blocking any step of this signalling cascade inhibits Hh signalling and correspondingly suppresses the growth of both, fly and human cancer cells harbouring oncogenic Ras mutations. These findings highlight a non-canonical Egfr signalling mechanism, centered on Arf6 as a novel regulator of Hh signalling. This explains both, the puzzling requirement of Egfr in oncogenic Ras-mediated overgrowth and the cooperation between Egfr and Hedgehog.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, Connecticut 06536, USA.
authors.forename: Chiswili
authors.initials: C
authors.lastname: Chabu
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, Connecticut 06536, USA.
authors.forename: Da-Ming
authors.initials: DM
authors.lastname: Li
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, Connecticut 06536, USA.|Children's Hospital &Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai 20043, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D060227:Imaginal Discs / Q000378:metabolism / Q000473:pathology; D007814:Larva / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018010:Receptors, Invertebrate Peptide / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000089982:ADP-Ribosylation Factor 6; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D018010:Receptors, Invertebrate Peptide; D049452:Green Fluorescent Proteins; C077245:hh protein, Drosophila; D007168:IMP Dehydrogenase; C000609465:ras protein, Drosophila; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human