ESCRT-0 is not required for ectopic Notch activation and tumor suppression in Drosophila.
Multivesicular endosome (MVE) sorting depends on proteins of the Endosomal Sorting Complex Required for Transport (ESCRT) family. These are organized in four complexes (ESCRT-0, -I, -II, -III) that act in a sequential fashion to deliver ubiquitylated cargoes into the internal luminal vesicles (ILVs) of the MVE. Drosophila genes encoding ESCRT-I, -II, -III components function in sorting signaling receptors, including Notch and the JAK/STAT signaling receptor Domeless. Loss of ESCRT-I, -II, -III in Drosophila epithelia causes altered signaling and cell polarity, suggesting that ESCRTs genes are tumor suppressors. However, the nature of the tumor suppressive function of ESCRTs, and whether tumor suppression is linked to receptor sorting is unclear. Unexpectedly, a null mutant in Hrs, encoding one of the components of the ESCRT-0 complex, which acts upstream of ESCRT-I, -II, -III in MVE sorting is dispensable for tumor suppression. Here, we report that two Drosophila epithelia lacking activity of Stam, the other known components of the ESCRT-0 complex, or of both Hrs and Stam, accumulate the signaling receptors Notch and Dome in endosomes. However, mutant tissue surprisingly maintains normal apico-basal polarity and proliferation control and does not display ectopic Notch signaling activation, unlike cells that lack ESCRT-I, -II, -III activity. Overall, our in vivo data confirm previous evidence indicating that the ESCRT-0 complex plays no crucial role in regulation of tumor suppression, and suggest re-evaluation of the relationship of signaling modulation in endosomes and tumorigenesis.
IFOM, Istituto FIRC di Oncologia Molecolare @ IFOM-IEO Campus, Milano, Italy.
Emiliana
E
Tognon
IFOM, Istituto FIRC di Oncologia Molecolare @ IFOM-IEO Campus, Milano, Italy.
Nadine
N
Wollscheid
DIMES, Dipartimento di Medicina Sperimentale, Anatomia Umana, Università di Genova, Genova, Italy.
Katia
K
Cortese
DIMES, Dipartimento di Medicina Sperimentale, Anatomia Umana, Università di Genova, Genova, Italy; Experimental Imaging Center, Scientific Institute San Raffaele, Milano, Italy.
Carlo
C
Tacchetti
IFOM, Istituto FIRC di Oncologia Molecolare @ IFOM-IEO Campus, Milano, Italy.
Thomas
T
Vaccari
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002872:Chromosome Deletion; D059006:Chromosomes, Insect / Q000235:genetics; D029721:Drosophila Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011992:Endosomes / Q000502:physiology* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000378:metabolism*; D005123:Eye / Q000254:growth & development / Q000473:pathology; D005260:Female; D016147:Genes, Tumor Suppressor; D005816:Genetic Complementation Test; D060227:Imaginal Discs / Q000378:metabolism / Q000473:pathology; D009030:Mosaicism; D006080:Ovarian Follicle / Q000473:pathology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D018123:Receptors, Interleukin / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C497759:N protein, Drosophila; D010750:Phosphoproteins; D018123:Receptors, Interleukin; D051880:Receptors, Notch; C524045:STAM protein, Drosophila; D025521:Tumor Suppressor Proteins; C444499:dome protein, Drosophila; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C081435:l(2)gl protein, Drosophila