JCB logo
amgmicro.com
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published 23 June 2003. doi:10.1083/jcb.200212158
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 519K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gu, H.
Right arrow Articles by Neel, B. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gu, H.
Right arrow Articles by Neel, B. G.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

© The Rockefeller University Press, 0021-9525/2003/6/1151 $5.00
The Journal of Cell Biology, Volume 161, Number 6, 1151-1161

Article

Critical role for scaffolding adapter Gab2 in Fc{gamma}R-mediated phagocytosis



Haihua Gu1, Roberto J. Botelho2, Min Yu1, Sergio Grinstein2 and Benjamin G. Neel1

1 Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115
2 Program in Cell Biology, Hospital for Sick Children and Department of Biochemistry, University of Toronto, Toronto, Ontario M5G1X8, Canada

Address correspondence to Haihua Gu, Harvard Institutes of Medicine, 77 Ave. Louis Pasteur, HIM 1047 Boston, MA 02115. Tel.: (617) 667-0908. Fax: (617) 667-0610. E-mail: hgu{at}caregroup.harvard.edu

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 Fc{gamma} receptor (Fc{gamma}R)–initiated phagocytosis in macrophages. Upon Fc{gamma}R activation, Gab2 becomes tyrosyl phosphorylated and associated with p85, the regulatory subunit of phosphoinositide 3-kinase (PI3K), and the protein–tyrosine phosphatidylinositol Shp-2. Fc{gamma}R-mediated phagocytosis is severely impaired in bone marrow–derived macrophages from Gab2-/- mice. The defect in phagocytosis correlates with decreased Fc{gamma}R-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 Fc{gamma}R-mediated phagocytosis, our results indicate that Gab2 acts as a key component of Fc{gamma}R-mediated phagocytosis, most likely by amplifying PI3K signaling in the nascent phagosome.

Key Words: macrophages; PI3K; phagocytosis; Fc{gamma}R; PH domain

H. Gu and R.J. Botelho contributed equally to this work.

The online version of this article contains supplemental material.

* Abbreviations used in this paper: BMM, bone marrow–derived macrophages; Fc{gamma}R, Fc{gamma} receptor; Gab2, Grb2-associated binder 2; ITAM, immune receptor–based tyrosine motif; PH, pleckstrin homology; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol-3,4,5-trisphosphate; RAW, RAW 264.7; SFK, Src family tyrosine kinase; WT, wild type; Wort, wortmannin.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents