The adapter molecule Gab2 regulates Fc epsilon RI-mediated signal transduction in mast cells.
The recently cloned scaffolding molecule Gab2 can assemble multiple molecules involved in signaling pathways. Bone marrow-derived mast cells isolated from Gab2(-/-) mice have defective signaling probably due to the lack of the activation of phosphatidylinositol-3 kinase (PI3-kinase). In this study, we investigated the role of Gab2 using the rat basophilic leukemia 2H3 cell line mast cells. Fc epsilon RI aggregation induced the tyrosine phosphorylation of Gab2 and translocation of a significant fraction of it from the cytosol to the plasma membrane. As in other cells, Gab2 was found to associate with several signaling molecules including Src homology 2-containing protein tyrosine phosphatase 2, Grb2, Lyn, and phospholipase C gamma (PLC gamma). The association of Gab2 with Lyn and PLC gamma were enhanced after receptor aggregation. Overexpression of Gab2 in rat basophilic leukemia 2H3 cell line cells inhibited the Fc epsilon RI-induced tyrosine phosphorylation of the subunits of the receptor, and the phosphorylation and/or activation of Syk and mitogen-activated protein kinase. Downstream events such as calcium mobilization, degranulation, and induction of TNF-alpha and IL-6 gene transcripts were decreased in Gab2 overexpressing cells, although Akt phosphorylation as a measure of PI3-kinase activation was unaffected. These results suggest that in addition to the positive effects mediated by PI3-kinase that are apparent in Gab2(-/-) mast cells, Gab2 by interacting with Lyn and PLC gamma may have negative regulatory effects on Fc epsilon RI-induced mast cell signaling and functions.
Xie
Zhi-Hui
ZH
Receptors and Signal Transduction Section, Oral Infection and Immunity Branch, Department of Health and Human Services, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Ambudkar
Indu
I
Siraganian
Reuben P
RP
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006636:Histamine Release; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000276:immunology*; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017455:Receptors, IgE / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C490893:Gab2 protein, rat; D007527:Isoenzymes; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017455:Receptors, IgE; D019000:Phosphotyrosine; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium