Journal
JOURNAL OF IMMUNOLOGY
Volume 176, Issue 4, Pages 2421-2429Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.176.4.2421
Keywords
-
Categories
Ask authors/readers for more resources
Scaffolding adapter Grb2-associated binder 2 (Gab2) is a key component of Fc is an element of RI signaling in mast cells, required for the activation of PI3K. To understand how Gab2 is activated in Fc is an element of RI signaling, we asked which protein tyrosine kinase is required for Gab2 phosphorylation. We found that Gab2 tyrosyl phosphorylation requires Lyn and Silk. In agreement with published results, we found that Fyn also contributes to Gab2 tyrosyl phosphorylation. However, Syk activation is defective in Fyn(-/-) mast cells, suggesting that Syk is the proximal kinase responsible for Gab2 tyrosyl phosphorylation. Then, we asked which domains in Gab2 are required for Gab2 tyrosyl phosphorylation. We found that the Grb2-Src homology 3 (SH3) binding sites are required for, whereas the pleckstrin homology (PH) domain contributes to, Gab2 tyrosyl phosphorylation. Using a protein/lipid overlay assay, we determined that the Gab2 PH domain preferentially binds the PI3K lipid products, PI3, 4,5P3 and PI3, 4P2. Furthermore, the Grb2-SH3 binding sites and PH domain binding to PI3K lipid products are required for Gab2 function in Fc is an element of RI-evoked degranulation and Akt activation. Our data strongly suggest a model for Gab2 action in Fc is an element of RI signaling. The Grb2 SH3 binding sites play a critical role in bringing Gab2 to Fc is an element of RI, whereupon Gab2 becomes tyrosyl-phosphorylated in a Syk-dependent fashion. Phosphorylated Gab2 results in recruitment and activation of PI3K, whose lipid products bind the PH domain of Gab2 and acts in positive feedback loop for sustained PI3K recruitment and phosphatidylinositol-3,4,5-trispbosphate production, required for Fc is an element of RI-evoked degranulation of mast cells.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available