title: ESCRT-0 complex modulates Rbf-mutant cell survival by regulating Rhomboid endosomal trafficking and EGFR signaling.
abstract: The Rb tumor suppressor is conserved in Drosophila, and its inactivation can lead to cell proliferation or death depending on the specific cellular context. Therefore, identifying genes that affect the survival of Rb-mutant cells can potentially identify novel targets for therapeutic intervention in cancer. From a genetic screen in Drosophila, we identified synthetic lethal interactions between mutations of fly Rb (rbf) and the ESCRT-0 components stam and hrs We show that inactivation of ESCRT-0 sensitizes rbf-mutant cells to undergo apoptosis through inhibition of EGFR signaling and accumulation of Hid protein. Mutation of stam inhibits EGFR signaling upstream of secreted Spi and downstream of Rhomboid expression, and causes Rhomboid protein to accumulate in the abnormal endosomes labeled with both the early and late endosomal markers Rab5 and Rab7. These results reveal that ESCRT-0 mutants inhibit EGFR signaling by disrupting Rhomboid endosomal trafficking in the ligand-producing cells. Because ESCRT-0 also plays crucial roles in EGFR downregulation after ligand binding, this study provides new insights into how loss of ESCRT-0 function can either increase or decrease EGFR signaling.
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, 929 E. 57th Street, Chicago, IL 60637, USA.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Sheng
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, No.1 Beichen West Road, Chaoyang District, Beijing 100101, People's Republic of China.
authors.forename: Lijia
authors.identifier: 0000-0001-6735-9569
authors.initials: L
authors.lastname: Yu
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, 929 E. 57th Street, Chicago, IL 60637, USA.
authors.forename: Tianyi
authors.identifier: 0000-0002-2833-3363
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, 929 E. 57th Street, Chicago, IL 60637, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Pei
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, 929 E. 57th Street, Chicago, IL 60637, USA.
authors.forename: Xuan
authors.identifier: 0000-0003-4830-7311
authors.initials: X
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, No.1 Beichen West Road, Chaoyang District, Beijing 100101, People's Republic of China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, 929 E. 57th Street, Chicago, IL 60637, USA wei@uchicago.edu.
authors.forename: Wei
authors.identifier: 0000-0003-3962-370X
authors.initials: W
authors.lastname: Du
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics*; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics*; D018010:Receptors, Invertebrate Peptide / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D010750:Phosphoproteins; C410303:RB protein, Drosophila; D018010:Receptors, Invertebrate Peptide; C081481:Rho protein, Drosophila; C524045:STAM protein, Drosophila; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C076026:spi protein, Drosophila; D004815:Epidermal Growth Factor; C066532:Egfr protein, Drosophila; D066246:ErbB Receptors
keywords: Apoptosis; EGFR signaling; Hrs; Rbf; Rhomboid; Stam