Adapter molecule Grb2-associated binder 1 is specifically expressed in marginal zone B cells and negatively regulates thymus-independent antigen-2 responses.
Grb2-associated binder 1 (Gab1) is a member of the Gab/daughter of sevenless family of adapter molecules involved in the signal transduction pathways of a variety of growth factors, cytokines, and Ag receptors. To know the role for Gab1 in hematopoiesis and immune responses in vivo, we analyzed radiation chimeras reconstituted with fetal liver (FL) cells of Gab1(-/-) mice, because Gab1(-/-) mice are lethal to embryos. Transfer of Gab1(-/-) FL cells of 14.5 days post-coitum rescued lethally irradiated mice, indicating that Gab1 is not essential for hematopoiesis. Although mature T and B cell subsets developed normally in the peripheral lymphoid organs, reduction of pre-B cells and increase of myeloid cells in the Gab1(-/-) FL chimeras suggested the regulatory roles for Gab1 in hematopoiesis. The chimera showed augmented IgM and IgG1 production to thymus-independent (TI)-2 Ag, although they showed normal responses for thymus-dependent and TI-1 Ags, indicating its negative role specific to TI-2 response. Gab1(-/-) splenic B cells stimulated with anti-delta-dextran plus IL-4 plus IL-5 showed augmented IgM and IgG1 production in vitro that was corrected by the retrovirus-mediated transfection of the wild-type Gab1 gene, clearly demonstrating the cell-autonomous, negative role of Gab1. Furthermore, we showed that the negative role of Gab1 required its Src homology 2-containing tyrosine phosphatase-2 binding sites. Cell fractionation analysis revealed that nonfollicular B cells were responsible for the augmented Ab production in vitro. Consistent with these results, the Gab1 gene was expressed in marginal zone B cells but not follicular B cells. These results indicated that Gab1 is a unique negative regulator specific for TI-2 responses.
Itoh
Shousaku
S
Department of Molecular Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Itoh
Motoyuki
M
Nishida
Keigo
K
Yamasaki
Satoru
S
Yoshida
Yuichi
Y
Narimatsu
Masahiro
M
Park
Sung Joo
SJ
Hibi
Masahiko
M
Ishihara
Katsuhiko
K
Hirano
Toshio
T
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000955:Antigens, T-Independent / Q000276:immunology*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites; D002478:Cells, Cultured; D003911:Dextrans / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology*; D016332:Fetal Tissue Transplantation; D051380:GRB2 Adaptor Protein; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D007136:Immunoglobulins / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D054648:Protein Phosphatase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011828:Radiation Chimera; D013154:Spleen / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000955:Antigens, T-Independent; D003911:Dextrans; D051380:GRB2 Adaptor Protein; C490897:Gab1 protein, mouse; C495949:Grb2 protein, mouse; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011506:Proteins; D054648:Protein Phosphatase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse