NORMAL GENOMIC

• Myung PS, Boerthe NJ, Koretzky GA
• Adapter proteins in lymphocyte antigen-receptor signaling.
• Curr Opin Immunol. 2000; 12: 256-66
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• Adapter molecules contain discrete modular domains that direct specific intermolecular interactions to orchestrate assembly of signaling complexes. A number of adapter proteins play critical roles in both positive and negative regulation of antigen-receptor signaling, influencing lymphocyte development and function.

• Du Pasquier L
• The phylogenetic origin of antigen-specific receptors.
• Curr Top Microbiol Immunol. 2000; 248: 160-85

• Gaul BS, Harrison ML, Geahlen RL, Burton RA, Post CB
• Substrate recognition by the Lyn protein-tyrosine kinase. NMR structure of the immunoreceptor tyrosine-based activation motif signaling region of the B cell antigen receptor.
• J Biol Chem. 2000; 275: 16174-82
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• The immunoreceptor tyrosine-based activation motif (ITAM) plays a central role in transmembrane signal transduction in hematopoietic cells by mediating responses leading to proliferation and differentiation. An initial signaling event following activation of the B cell antigen receptor is phosphorylation of the CD79a (Ig-alpha) ITAM by Lyn, a Src family protein-tyrosine kinase. To elucidate the structural basis for recognition between the ITAM substrate and activated Lyn kinase, the structure of an ITAM-derived peptide bound to Lyn was determined using exchange-transferred nuclear Overhauser NMR spectroscopy. The bound substrate structure has an irregular helix-like character. Docking based on the NMR data into the active site of the closely related Lck kinase strongly favors ITAM binding in an orientation similar to binding of cyclic AMP-dependent protein kinase rather than that of insulin receptor tyrosine kinase. The model of the complex provides a rationale for conserved ITAM residues, substrate specificity, and suggests that substrate binds only the active conformation of the Src family tyrosine kinase, unlike the ATP cofactor, which can bind the inactive form.

• Denny MF, Patai B, Straus DB
• Differential T-cell antigen receptor signaling mediated by the Src family kinases Lck and Fyn.
• Mol Cell Biol. 2000; 20: 1426-35
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• Src family tyrosine kinases play a key role in T-cell antigen receptor (TCR) signaling. They are responsible for the initial tyrosine phosphorylation of the receptor, leading to the recruitment of the ZAP-70 tyrosine kinase, as well as the subsequent phosphorylation and activation of ZAP-70. Molecular and genetic evidence indicates that both the Fyn and Lck members of the Src family can participate in TCR signal transduction; however, it is unclear to what extent they utilize the same signal transduction pathways and activate the same downstream events. We have addressed this issue by examining the ability of Fyn to mediate TCR signal transduction in an Lck-deficient T-cell line (JCaM1). Fyn was able to induce tyrosine phosphorylation of the TCR and recruitment of the ZAP-70 kinase, but the pattern of TCR phosphorylation was altered and activation of ZAP-70 was defective. Despite this, the SLP-76 adapter protein was inducibly tyrosine phosphorylated, and both the Ras-mitogen-activated protein kinase and the phosphatidylinositol 4, 5-biphosphate signaling pathways were activated. TCR stimulation of JCaM1/Fyn cells induced the expression of the CD69 activation marker and inhibited cell growth, but NFAT activation and the production of interleukin-2 were markedly reduced. These results indicate that Fyn mediates an alternative form of TCR signaling which is independent of ZAP-70 activation and generates a distinct cellular phenotype. Furthermore, these findings imply that the outcome of TCR signal transduction may be determined by which Src family kinase is used to initiate signaling.

• DeFranco AL
• Transmembrane signaling by antigen receptors of B and T lymphocytes.
• Curr Opin Cell Biol. 1995; 7: 163-75
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• The specificity of immune responses depends upon the activation of only those lymphocytes that recognize the introduced antigen. In recent years, a great deal has been learned about the structure of lymphocyte receptors for antigens and about their signal transduction mechanism. These receptors activate intracellular protein tyrosine kinases of at least two families, the Src family and the Syk/ZAP-70 family. Recent studies have given us considerable insight into the interactions of these two types of kinases and how they mediate antigen receptor signaling.

• Gold MR, Matsuuchi L
• Signal transduction by the antigen receptors of B and T lymphocytes.
• Int Rev Cytol. 1995; 157: 181-276
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• B and T lymphocytes of the immune system recognize and destroy invading microorganisms but are tolerant to the cells and tissues of one's own body. The basis for this self/non-self-discrimination is the clonal nature of the B and T cell antigen receptors. Each lymphocyte has antigen receptors with a single unique antigen specificity. Multiple mechanisms ensure that self-reactive lymphocytes are eliminated or silenced whereas lymphocytes directed against foreign antigens are activated only when the appropriate antigen is present. The key element in these processes is the ability of the antigen receptors to transmit signals to the interior of the lymphocyte when they bind the antigen for which they are specific. Whether these signals lead to activation, tolerance, or cell death is dependent on the maturation state of the lymphocytes as well as on signals from other receptors. We review the role of antigen receptor signaling in the development and activation of B and T lymphocytes and also describe the biochemical signaling mechanisms employed by these receptors. In addition, we discuss how signal transduction pathways activated by the antigen receptors may alter gene expression, regulate the cell cycle, and induce or prevent programmed cell death.

• Kim KM, Reth M
• Signaling difference between class IgM and IgD antigen receptors.
• Ann N Y Acad Sci. 1995; 766: 81-8
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• Most mature B lymphocytes coexpress two classes of antigen receptor, IgM and IgD. The differences in the signal transduction from the two receptors are still a matter of controversy. We have analyzed B-cell lines expressing IgM or IgD antigen receptors with the same antigen specificity. Cross-linking of these receptors with either antigen or class-specific antibodies results in the activation of protein tyrosine kinases and the phosphorylation of the same substrate proteins. The kinetic and intensity of phosphorylation, however, was quite different between the two receptors when they were cross-linked by antigen. In membrane IgM-expressing cells, the substrate phosphorylation reached a maximum after one minute and diminished after 60 minutes, whereas in the membrane IgD-expressing cells, the substrate phosphorylation increased further over time, reaching its maximum at 60 minutes and persisting longer than 240 minutes after exposure to antigen. Recently prolonged signaling has been found to be responsible for signaling differences between tyrosine kinase receptors using otherwise similar signaling routes. Thus, the duration of a signal may be an important biological feature of signal-transducing cascades.

• Cambier JC, Jensen WA
• The hetero-oligomeric antigen receptor complex and its coupling to cytoplasmic effectors.
• Curr Opin Genet Dev. 1994; 4: 55-63
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• T-cell and B-cell antigen receptors are representative of a family of multisubunit receptors that utilize Src-family kinases as proximal cytoplasmic effectors in signal transduction. Recent studies have shown that distinct receptor subunits mediate ligand and effector interactions and demonstrate that physical interaction with effectors, and their activation, is a function of a 26 amino acid motif found in multiple receptor subunits. Further, receptor ligation induces tyrosine phosphorylation of this motif, and this initiates SH2-mediated association and activation of Src-family kinases and, apparently, ZAP70 kinases. Finally, this association triggers SH3-mediated binding of Lyn and Fyn to PI3-K, resulting in PI3-K activation. An integrated model of signal transduction is presented.