Essential role for Gab2 in the allergic response

Haihua Gu (), Kan Saito, Lori D. Klaman, Junqing Shen, Tony Fleming, YongPing Wang, Joanne C. Pratt, Guosheng Lin, Bing Lim, Jean-Pierre Kinet and Benjamin G. Neel
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Haihua Gu: Cancer Biology Program
Kan Saito: Beth Israel Deaconess Medical Center and Harvard Medical School
Lori D. Klaman: Cancer Biology Program
Junqing Shen: Cancer Biology Program
Tony Fleming: Beth Israel Deaconess Medical Center and Harvard Medical School
YongPing Wang: Cancer Biology Program
Joanne C. Pratt: Franklin W. Olin College of Engineering
Guosheng Lin: Cancer Biology Program
Bing Lim: Cancer Biology Program
Jean-Pierre Kinet: Beth Israel Deaconess Medical Center and Harvard Medical School
Benjamin G. Neel: Cancer Biology Program

Nature, 2001, vol. 412, issue 6843, 186-190

Abstract: Abstract Dos/Gab family scaffolding adapters (Dos, Gab1, Gab2) bind several signal relay molecules, including the protein-tyrosine phosphatase Shp-2 and phosphatidylinositol-3-OH kinase (PI(3)K); they are also implicated in growth factor, cytokine and antigen receptor signal transduction1. Mice lacking Gab1 die during embryogenesis and show defective responses to several stimuli2,3. Here we report that Gab2-/- mice are viable and generally healthy; however, the response (for example, degranulation and cytokine gene expression) of Gab2-/- mast cells to stimulation of the high affinity immunoglobulin-ε (IgE) receptor FcεRI is defective. Accordingly, allergic reactions such as passive cutaneous and systemic anaphylaxis are markedly impaired in Gab2-/- mice. Biochemical analyses reveal that signalling pathways dependent on PI(3)K, a critical component of FcεRI signalling, are defective in Gab2-/- mast cells. Our data identify Gab2 as the principal activator of PI(3)K in response to FcεRI activation, thereby providing genetic evidence that Dos/Gab family scaffolds regulate the PI(3)K pathway in vivo. Gab2 and/or its associated signalling molecules may be new targets for developing drugs to treat allergy.

Date: 2001
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DOI: 10.1038/35084076

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