Dual phosphorylation of phosphoinositide 3-kinase adaptor Grb2-associated binder 2 is responsible for superoxide formation synergistically stimulated by Fc gamma and formyl-methionyl-leucyl-phenylalanine receptors in differentiated THP-1 cells.
The class Ia phosphoinositide (PI) 3-kinase consisting of p110 catalytic and p85 regulatory subunits is activated by Tyr kinase-linked membrane receptors such as FcgammaRII through the association of p85 with the phosphorylated receptors or adaptors. The heterodimeric PI 3-kinase is also activated by G protein-coupled chemotactic fMLP receptors, and activation ... of the lipid kinase plays an important role in various immune responses, including superoxide formation in neutrophils. Although fMLP-induced superoxide formation is markedly enhanced in FcgammaRII-primed neutrophils, the molecular mechanisms remain poorly characterized. In this study, we identified two Tyr-phosphorylated proteins, c-Cbl (Casitas B-lineage lymphoma) and Grb2-associated binder 2 (Gab2), as PI 3-kinase adaptors that are Tyr phosphorylated upon the stimulation of FcgammaRII in differentiated neutrophil-like THP-1 cells. Interestingly, Gab2 was, but c-Cbl was not, further Ser/Thr phosphorylated by fMLP. Thus, the adaptor Gab2 appeared to be dually phosphorylated at the Ser/Thr and Tyr residues through the two different types of membrane receptors. The Ser/Thr phosphorylation of Gab2 required the activation of extracellular signal-regulated kinase, and fMLP receptor stimulation indeed activated extracellular signal-regulated kinase in the cells. Enhanced superoxide formation in response to Fcgamma and fMLP was markedly attenuated when the Gab2 Ser/Thr phosphorylation was inhibited. These results show the importance of the dual phosphorylation of PI 3-kinase adaptor Gab2 for the enhanced superoxide formation in neutrophil-type cells.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Carrier Proteins, Cell Differentiation, Cell Line, Cross-Linking Reagents, Drug Synergism, Flavonoids, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Mitogen-Activated Protein Kinases, N-Formylmethionine Leucyl-Phenylalanine, Neutrophils, Phosphatidylinositol 3-Kinases, Phosphatidylinositol Phosphates, Phosphorylation, Protein-Tyrosine Kinases, Receptors, Formyl Peptide, Receptors, IgG, Serine, Superoxides, Threonine
Adaptor Proteins, Signal Transducing, Carrier Proteins, Cell Differentiation, Cell Line, Cross-Linking Reagents, Drug Synergism, Flavonoids, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Mitogen-Activated Protein Kinases, N-Formylmethionine Leucyl-Phenylalanine, Neutrophils, Phosphatidylinositol 3-Kinases, Phosphatidylinositol Phosphates, Phosphorylation, Protein-Tyrosine Kinases, Receptors, Formyl Peptide, Receptors, IgG, Serine, Superoxides, Threonine
J. Immunol.
Date: Oct. 15, 2003
PubMed ID: 14530346
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