Disease relevance of Gab2

• As pharmacological targeting of Gab2 in mast cells is a potential strategy to treat allergy, our results suggest prudence, as NK cells may participate in IgE-mediated anaphylaxis in a Gab2-independent manner [1].
• Accordingly, allergic reactions such as passive cutaneous and systemic anaphylaxis are markedly impaired in Gab2-/- mice [2].
• 2. Mice immunized with the anti-idiotype demonstrate delayed-type hypersensitivity reactions when challenged with melanoma (p97-positive) tumor cells [3].
• Ablation of Gab2 severely suppressed lung metastasis [4].

High impact information on Gab2

• 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 transduction [2].
• Biochemical analyses reveal that signalling pathways dependent on PI(3)K, a critical component of Fc(epsilon)RI signalling, are defective in Gab2-/- mast cells [2].
• 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-epsilon (IgE) receptor Fc(epsilon)RI is defective [2].
• Cloning of p97/Gab2, the major SHP2-binding protein in hematopoietic cells, reveals a novel pathway for cytokine-induced gene activation [5].
• Gab2-deficient mast cells were severely impaired in chemokine mRNA induction whereas LAT-deficient mast cells showed a more pronounced defect in cytokines [6].

Biological context of Gab2

• G-CSF-induced tyrosine phosphorylation of Gab2 occurred in the wild-type and single Y-to-F mutants (Y704F, Y729F, and Y744F), but not in the ADA and W650R loss-of-function mutants [7].
• Grb2-associated binder 2 (Gab2) is a scaffolding protein required for FcgammaR-initiated allergic responses in mast cells and FcgammaR-mediated phagocytosis in macrophages, where it links IgE and IgG receptors to the phosphatidylinositol-3 kinase (PI-3K) pathway [1].
• We show here that mouse NK cells express Gab2 and that although PI-3K was required for ADCC, this FcgammaR-mediated function was normal in Gab2-/- NK cells [1].
• The Grb2 binding site on Gab2 also plays an auxiliary role in recruitment to the phagosome [8].
• In EC cells, Gab2 silencing results in hypersensitivity to RA-induced apoptosis and abrogates the protection by bFGF [9].

Anatomical context of Gab2

• Phosphorylation of Gab2 occurred in wild-type, but not Lyn-deficient, G-CSFR-transfected DT40 B cells [7].
• Moreover, NK cell development, spontaneous cytotoxicity, and responses to and production of cytokines were not perturbed in Gab2-/- mice [1].
• FcgammaR-mediated phagocytosis is severely impaired in bone marrow-derived macrophages from Gab2-/- mice [8].
• Using confocal fluorescence microscopy, we find that Gab2 is recruited to the nascent phagosome, where de novo PI3K lipid production occurs [8].
• The in vivo significance of this association is illustrated by the fact that T-cell responses are impaired in transgenic mice expressing wild-type Gab2 but not in mice expressing mutant Gab2 lacking the motif [10].

Associations of Gab2 with chemical compounds

• Our findings provide the first evidence that Gab2 is an important player in neural differentiation, partly by acting downstream of bFGF to mediate survival through phosphoinositide 3 kinase-AKT [9].
• A novel role for Gab2 in bFGF-mediated cell survival during retinoic acid-induced neuronal differentiation [9].
• Since this association involves the proline-rich sequences of Gab2, it probably involves the Src homology 3 domain of Src kinase [11].

Regulatory relationships of Gab2

• Overexpression of mutants of Grb2 with inactive SH2 or SH3 domains also blocks cytokine-stimulated Gab2 phosphorylation [12].
• Epidermal growth factor-induced phosphatidylinositol 3-kinase activation and DNA synthesis. Identification of Grb2-associated binder 2 as the major mediator in rat hepatocytes [13].

Other interactions of Gab2

• Scaffolding adapter Grb2-associated binder 2 requires Syk to transmit signals from FcepsilonRI [14].
• Cells expressing truncated proximal G-CSFR, the tyrosine-null (Y4F) G-CSFR, or Y764F mutant receptors had decreased phosphorylation of Gab2 [7].
• In agreement with published results, we found that Fyn also contributes to Gab2 tyrosyl phosphorylation [14].
• The scaffolding proteins Gab1 and/or Gab2 were candidates for this role [15].
• Analysis of Y-->F and "add-back" mutants of betac shows that Y577, the Shc binding site, is the major site required for Gab2 phosphorylation in response to cytokine stimulation [12].

References