Negative signaling in B cells causes reduced Ras activity by reducing Shc-Grb2 interactions.
To elucidate the molecular basis for inhibition of B cell proliferation and differentiation by the Fc receptor for IgG (Fc(gamma)RII), we compared the signaling events in B cells stimulated by cross-linking surface Ig alone (positive signaling), or by co-cross-linking surface Ig and Fc(gamma)RII (negative signaling). Both modes of stimulation induced tyrosine kinase activation. Positive signaling induced activation of Ras, Raf-1 kinase, and mitogen-activated protein kinase; these events were significantly attenuated during negative signaling. Since Ras is activated by SOS and Vav, two known guanine nucleotide exchange factors, activation events associated with these molecules using the two different stimuli were examined. Results of these experiments indicated that tyrosine phosphorylation of Vav did not change upon co-cross-linking. In contrast, the association of Shc and Grb2 was abrogated under negative and induced under positive signaling conditions. Concomitantly, Shc was observed to associate with a tyrosine-phosphorylated 145-kDa protein, previously identified as Src homology 2-containing inositol phosphatase, only under conditions of negative signaling. Based on these results, we hypothesize that negative signaling via the Fc(gamma)RII in B cells is at least partly the result of a block in Ras activation, and that SOS, but not Vav, is the major guanine nucleotide exchange factor in B cells for Ras activation.
Tridandapani
S
S
Department of Microbiology, Ohio State University, Columbus 43210, USA.
Chacko
G W
GW
Van Brocklyn
J R
JR
Coggeshall
K M
KM
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D051380:GRB2 Adaptor Protein; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D018797:Cell Cycle Proteins; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C496619:Vav1 protein, mouse; D019000:Phosphotyrosine; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D016283:Proto-Oncogene Proteins p21(ras)