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Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23

BACKGROUND: The Drosophila abnormal wing discs (awd) belongs to a highly conserved family of genes implicated in metastasis suppression, metabolic homeostasis and epithelial morphogenesis. The cellular function of the mammalian members of this family, the Nm23 proteins, has not yet been clearly defi...

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Autores principales: Ignesti, Marilena, Barraco, Marilena, Nallamothu, Gouthami, Woolworth, Julie A, Duchi, Serena, Gargiulo, Giuseppe, Cavaliere, Valeria, Hsu, Tien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937027/
https://www.ncbi.nlm.nih.gov/pubmed/24528630
http://dx.doi.org/10.1186/1741-7007-12-12
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author Ignesti, Marilena
Barraco, Marilena
Nallamothu, Gouthami
Woolworth, Julie A
Duchi, Serena
Gargiulo, Giuseppe
Cavaliere, Valeria
Hsu, Tien
author_facet Ignesti, Marilena
Barraco, Marilena
Nallamothu, Gouthami
Woolworth, Julie A
Duchi, Serena
Gargiulo, Giuseppe
Cavaliere, Valeria
Hsu, Tien
author_sort Ignesti, Marilena
collection PubMed
description BACKGROUND: The Drosophila abnormal wing discs (awd) belongs to a highly conserved family of genes implicated in metastasis suppression, metabolic homeostasis and epithelial morphogenesis. The cellular function of the mammalian members of this family, the Nm23 proteins, has not yet been clearly defined. Previous awd genetic analyses unraveled its endocytic role that is required for proper internalization of receptors controlling different signaling pathways. In this study, we analyzed the role of Awd in controlling Notch signaling during development. RESULTS: To study the awd gene function we used genetic mosaic approaches to obtain cells homozygous for a loss of function allele. In awd mutant follicle cells and wing disc cells, Notch accumulates in enlarged early endosomes, resulting in defective Notch signaling. Our results demonstrate that awd function is required before γ-secretase mediated cleavage since over-expression of the constitutively active form of the Notch receptor in awd mutant follicle cells allows rescue of the signaling. By using markers of different endosomal compartments we show that Notch receptor accumulates in early endosomes in awd mutant follicle cells. A trafficking assay in living wing discs also shows that Notch accumulates in early endosomes. Importantly, constitutively active Rab5 cannot rescue the awd phenotype, suggesting that awd is required for Rab5 function in early endosome maturation. CONCLUSIONS: In this report we demonstrate that awd is essential for Notch signaling via its endocytic role. In addition, we identify the endocytic step at which Awd function is required for Notch signaling and we obtain evidence indicating that Awd is necessary for Rab5 function. These findings provide new insights into the developmental and pathophysiological function of this important gene family.
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spelling pubmed-39370272014-02-28 Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23 Ignesti, Marilena Barraco, Marilena Nallamothu, Gouthami Woolworth, Julie A Duchi, Serena Gargiulo, Giuseppe Cavaliere, Valeria Hsu, Tien BMC Biol Research Article BACKGROUND: The Drosophila abnormal wing discs (awd) belongs to a highly conserved family of genes implicated in metastasis suppression, metabolic homeostasis and epithelial morphogenesis. The cellular function of the mammalian members of this family, the Nm23 proteins, has not yet been clearly defined. Previous awd genetic analyses unraveled its endocytic role that is required for proper internalization of receptors controlling different signaling pathways. In this study, we analyzed the role of Awd in controlling Notch signaling during development. RESULTS: To study the awd gene function we used genetic mosaic approaches to obtain cells homozygous for a loss of function allele. In awd mutant follicle cells and wing disc cells, Notch accumulates in enlarged early endosomes, resulting in defective Notch signaling. Our results demonstrate that awd function is required before γ-secretase mediated cleavage since over-expression of the constitutively active form of the Notch receptor in awd mutant follicle cells allows rescue of the signaling. By using markers of different endosomal compartments we show that Notch receptor accumulates in early endosomes in awd mutant follicle cells. A trafficking assay in living wing discs also shows that Notch accumulates in early endosomes. Importantly, constitutively active Rab5 cannot rescue the awd phenotype, suggesting that awd is required for Rab5 function in early endosome maturation. CONCLUSIONS: In this report we demonstrate that awd is essential for Notch signaling via its endocytic role. In addition, we identify the endocytic step at which Awd function is required for Notch signaling and we obtain evidence indicating that Awd is necessary for Rab5 function. These findings provide new insights into the developmental and pathophysiological function of this important gene family. BioMed Central 2014-02-14 /pmc/articles/PMC3937027/ /pubmed/24528630 http://dx.doi.org/10.1186/1741-7007-12-12 Text en Copyright © 2014 Ignesti et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Ignesti, Marilena
Barraco, Marilena
Nallamothu, Gouthami
Woolworth, Julie A
Duchi, Serena
Gargiulo, Giuseppe
Cavaliere, Valeria
Hsu, Tien
Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23
title Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23
title_full Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23
title_fullStr Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23
title_full_unstemmed Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23
title_short Notch signaling during development requires the function of awd, the Drosophila homolog of human metastasis suppressor gene Nm23
title_sort notch signaling during development requires the function of awd, the drosophila homolog of human metastasis suppressor gene nm23
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937027/
https://www.ncbi.nlm.nih.gov/pubmed/24528630
http://dx.doi.org/10.1186/1741-7007-12-12
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