title: Lgl regulates Notch signaling via endocytosis, independently of the apical aPKC-Par6-Baz polarity complex.
abstract: BACKGROUND
  The Drosophila melanogaster junctional neoplastic tumor suppressor, Lethal-2-giant larvae (Lgl), is a regulator of apicobasal cell polarity and tissue growth. We have previously shown in the developing Drosophila eye epithelium that, without affecting cell polarity, depletion of Lgl results in ectopic cell proliferation and blockage of developmental cell death due to deregulation of the Hippo signaling pathway.
  
  
  RESULTS
  Here, we show that Notch signaling is increased in lgl-depleted eye tissue, independently of Lgl's function in apicobasal cell polarity. The upregulation of Notch signaling is ligand dependent and correlates with accumulation of cleaved Notch. Concomitant with higher cleaved Notch levels in lgl- tissue, early endosomes (Avalanche [Avl+]), recycling endosomes (Rab11+), early multivesicular bodies (Hrs+), and acidified vesicles, but not late endosomal markers (Car+ and Rab7+), accumulate. Colocalization studies revealed that Lgl associates with early to late endosomes and lysosomes. Upregulation of Notch signaling in lgl- tissue requires dynamin- and Rab5-mediated endocytosis and vesicle acidification but is independent of Hrs/Stam or Rab11 activity. Furthermore, Lgl regulates Notch signaling independently of the aPKC-Par6-Baz apical polarity complex.
  
  
  CONCLUSIONS
  Altogether, our data show that Lgl regulates endocytosis to restrict vesicle acidification and prevent ectopic ligand-dependent Notch signaling. This Lgl function is independent of the aPKC-Par6-Baz polarity complex and uncovers a novel attenuation mechanism of ligand-activated Notch signaling during Drosophila eye development.
authors.affiliation: Cell Cycle and Development Laboratory, Research Division, Peter MacCallum Cancer Centre, 7 St. Andrew's Place, East Melbourne, Melbourne, VIC 3002, Australia; Department of Genetics, University of Melbourne, 1-100 Grattan Street, Parkville, Melbourne, VIC 3010, Australia.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Parsons
authors.affiliation: Cell Cycle and Development Laboratory, Research Division, Peter MacCallum Cancer Centre, 7 St. Andrew's Place, East Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Marta
authors.initials: M
authors.lastname: Portela
authors.affiliation: Cell Cycle and Development Laboratory, Research Division, Peter MacCallum Cancer Centre, 7 St. Andrew's Place, East Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Grzeschik
authors.affiliation: Cell Cycle and Development Laboratory, Research Division, Peter MacCallum Cancer Centre, 7 St. Andrew's Place, East Melbourne, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, 7 St. Andrew's Place, East Melbourne, Melbourne, VIC 3002, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, 1-100 Grattan Street, Parkville, Melbourne, VIC 3010, Australia; Department of Anatomy and Neuroscience, University of Melbourne, 1-100 Grattan Street, Parkville, Melbourne, VIC 3010, Australia. Electronic address: helena.richardson@petermac.org.
authors.forename: Helena E
authors.initials: HE
authors.lastname: Richardson
mesh_terms: D000818:Animals; D054910:Compound Eye, Arthropod / Q000254:growth & development / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D004705:Endocytosis; D007814:Larva / Q000235:genetics / Q000254:growth & development / Q000502:physiology; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D029721:Drosophila Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; D025521:Tumor Suppressor Proteins; C081435:l(2)gl protein, Drosophila