The high affinity receptor for IgE on mast cells and basophils plays a central role in immediate hypersensitivity reactions. Reaction of receptor-bound IgE with polyvalent antigen clusters the receptors and this stimulates cellular secretion of both preformed and newly synthesized mediators of inflammation. Our studies focus on the molecular mechanisms by which aggregation of the receptors generate these cellular responses. The similarity of Fc(epsilon)RI to other receptors of the immune system (e.g. the clonotypic receptors on T and B lymphocytes), make it likely that the significance of such studies extends beyond the IgE/mast cell system. During the past year, our principal studies have been along five lines: 1) We have completed an initial characterization of the role of protein tyrosine phosphatases (PTP) in controlling the phosphorylation of the receptor. We found that the likely critical PTP are membrane bound and that they dephosphorylate aggregated receptors as actively as monomeric ones. When disaggregated both the receptors and several down stream targets are dephosphorylated by first order kinetics with rate constants that are very similar. These results and others suggest that the level of phosphorylation of Fc(epsilon)RI is largely controlled by the aggregation-induced activity of kinase(s) and not from changes in susceptibility to or activity of PTP. 2) We completed a direct analysis of the tyrosines on the receptors that become phosphorylated. We found: a) That it is the canonical tyrosines in the previously implicated """"""""ITAM"""""""" sequences within the cytoplasmic domains that are modified, b) That the in vitro phosphorylation by the receptor-associated kinase follows the same pattern as is observed in vivo, c) That one of the canonical tyrosines is much less phosphorylated than the five others. 3) We have completed a study on the role of limiting amounts of Lyn kinase as a controlling factor in signal transduction confirming a prior precdiction to that effect. 4) We have now developed a transfection system that allows us to analyze the interaction of Lyn kinase with the intact receptor by mutational analysis. 5) We have used the yeast """"""""two-hybrid"""""""" system to search for hitherto unrecognized proteins that may interact with the receptor.
| Metzger, Henry (2002) Molecular versatility of antibodies. Immunol Rev 185:186-205 |
| Hlavacek, W S; Redondo, A; Metzger, H et al. (2001) Kinetic proofreading models for cell signaling predict ways to escape kinetic proofreading. Proc Natl Acad Sci U S A 98:7295-300 |
| Liu, Z J; Haleem-Smith, H; Chen, H et al. (2001) Unexpected signals in a system subject to kinetic proofreading. Proc Natl Acad Sci U S A 98:7289-94 |
| Peirce, M; Metzger, H (2000) Detergent-resistant microdomains offer no refuge for proteins phosphorylated by the IgE receptor. J Biol Chem 275:34976-82 |
| Metzger, H; Chen, H; Goldstein, B et al. (1999) A quantitative approach to signal transduction. Immunol Lett 68:53-7 |
| Wofsy, C; Vonakis, B M; Metzger, H et al. (1999) One lyn molecule is sufficient to initiate phosphorylation of aggregated high-affinity IgE receptors. Proc Natl Acad Sci U S A 96:8615-20 |
| Metzger, H (1999) It's spring, and thoughts turn to...allergies. Cell 97:287-90 |
