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Critical role for scaffolding adapter Gab2 in FcγR-mediated phagocytosis

Grb2-associated binder 2 (Gab2), a member of the Dos/Gab subfamily scaffolding molecules, plays important roles in regulating the growth, differentiation, and function of many hematopoietic cell types. In this paper, we reveal a novel function of Gab2 in Fcγ receptor (FcγR)–initiated phagocytosis in...

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Autores principales: Gu, Haihua, Botelho, Roberto J., Yu, Min, Grinstein, Sergio, Neel, Benjamin G.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172986/
https://www.ncbi.nlm.nih.gov/pubmed/12821647
http://dx.doi.org/10.1083/jcb.200212158
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author Gu, Haihua
Botelho, Roberto J.
Yu, Min
Grinstein, Sergio
Neel, Benjamin G.
author_facet Gu, Haihua
Botelho, Roberto J.
Yu, Min
Grinstein, Sergio
Neel, Benjamin G.
author_sort Gu, Haihua
collection PubMed
description Grb2-associated binder 2 (Gab2), a member of the Dos/Gab subfamily scaffolding molecules, plays important roles in regulating the growth, differentiation, and function of many hematopoietic cell types. In this paper, we reveal a novel function of Gab2 in Fcγ receptor (FcγR)–initiated phagocytosis in macrophages. Upon FcγR activation, Gab2 becomes tyrosyl phosphorylated and associated with p85, the regulatory subunit of phosphoinositide 3-kinase (PI3K), and the protein–tyrosine phosphatidylinositol Shp-2. FcγR-mediated phagocytosis is severely impaired in bone marrow–derived macrophages from Gab2−/− mice. The defect in phagocytosis correlates with decreased FcγR-evoked activation of Akt, a downstream target of PI3K. Using confocal fluorescence microscopy, we find that Gab2 is recruited to the nascent phagosome, where de novo PI3K lipid production occurs. Gab2 recruitment requires the pleckstrin homology domain of Gab2 and is sensitive to treatment with the PI3K inhibitor wortmannin. The Grb2 binding site on Gab2 also plays an auxiliary role in recruitment to the phagosome. Because PI3K activity is required for FcγR-mediated phagocytosis, our results indicate that Gab2 acts as a key component of FcγR-mediated phagocytosis, most likely by amplifying PI3K signaling in the nascent phagosome.
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spelling pubmed-21729862008-05-01 Critical role for scaffolding adapter Gab2 in FcγR-mediated phagocytosis Gu, Haihua Botelho, Roberto J. Yu, Min Grinstein, Sergio Neel, Benjamin G. J Cell Biol Article Grb2-associated binder 2 (Gab2), a member of the Dos/Gab subfamily scaffolding molecules, plays important roles in regulating the growth, differentiation, and function of many hematopoietic cell types. In this paper, we reveal a novel function of Gab2 in Fcγ receptor (FcγR)–initiated phagocytosis in macrophages. Upon FcγR activation, Gab2 becomes tyrosyl phosphorylated and associated with p85, the regulatory subunit of phosphoinositide 3-kinase (PI3K), and the protein–tyrosine phosphatidylinositol Shp-2. FcγR-mediated phagocytosis is severely impaired in bone marrow–derived macrophages from Gab2−/− mice. The defect in phagocytosis correlates with decreased FcγR-evoked activation of Akt, a downstream target of PI3K. Using confocal fluorescence microscopy, we find that Gab2 is recruited to the nascent phagosome, where de novo PI3K lipid production occurs. Gab2 recruitment requires the pleckstrin homology domain of Gab2 and is sensitive to treatment with the PI3K inhibitor wortmannin. The Grb2 binding site on Gab2 also plays an auxiliary role in recruitment to the phagosome. Because PI3K activity is required for FcγR-mediated phagocytosis, our results indicate that Gab2 acts as a key component of FcγR-mediated phagocytosis, most likely by amplifying PI3K signaling in the nascent phagosome. The Rockefeller University Press 2003-06-23 /pmc/articles/PMC2172986/ /pubmed/12821647 http://dx.doi.org/10.1083/jcb.200212158 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Gu, Haihua
Botelho, Roberto J.
Yu, Min
Grinstein, Sergio
Neel, Benjamin G.
Critical role for scaffolding adapter Gab2 in FcγR-mediated phagocytosis
title Critical role for scaffolding adapter Gab2 in FcγR-mediated phagocytosis
title_full Critical role for scaffolding adapter Gab2 in FcγR-mediated phagocytosis
title_fullStr Critical role for scaffolding adapter Gab2 in FcγR-mediated phagocytosis
title_full_unstemmed Critical role for scaffolding adapter Gab2 in FcγR-mediated phagocytosis
title_short Critical role for scaffolding adapter Gab2 in FcγR-mediated phagocytosis
title_sort critical role for scaffolding adapter gab2 in fcγr-mediated phagocytosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172986/
https://www.ncbi.nlm.nih.gov/pubmed/12821647
http://dx.doi.org/10.1083/jcb.200212158
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