ABSTRACT Cells in the immune system are functionally connected with each other by a network of cell-cell communication. Crosslinkage of cell surface receptors with specific ligands/antigens is normally the initial event to start intracellular signal transduction for the communication. We here summarize the results of recent observations that suggest the existence of an alternative signalling pathway that starts by chemical reaction-mediated protein crosslinkage or structural modification. These reactions include oxidation of two thiol (SH) groups of cysteines on proteins to form disulfide (S-S) bonds and Schiff-base formation between carbonyl groups of sugar and lipid metabolites and amino groups of protein lysines. Oxidative microenvironments, which are created through production of reactive oxygen species (ROS) by inflammatory cells and actions of environmental elements such as ultraviolet (UV) light, X-rays, drugs and heavy metals, may initiate such an alternative pathway of signalling. Although there may be multiple primary sites of the redox-linked chemical reactions for signalling, we emphasize the crucial roles of cell surface receptor proteins and intracellular protein tyrosine kinases (PTKs) in the alternative pathway. Chemical reaction-mediated crosslinkage of cell surface receptor proteins, including glycosylphosphatidylinositol (GPI)-anchored proteins on T lymphocytes, has been shown to induce clustering of membrane lipid microdomains termed rafts and raft-associating signal transducing elements including Lck as a Src family PTK and production of ROS. Both non-receptor-type (Lck, Src) and receptor- type (EGFR, RET) PTKs have also been shown to be the direct targets of the redox-linked chemical reactions mediated by UV light, heavy metals and carbonyl compounds for initiating the signal transduction. Studies using mutant PTKs in which cysteines had been replaced by alanines showed that one or more cysteine in the C-terminal kinase domain, which is conserved among many PTKs, can be the critical target of chemical reactions. Structural modification by the chemical reactions may prime PTKs for autophosphorylation- dependent activation. The chemical reaction-mediated alternative pathway of cell signalling has been shown to bypass or modulate the non-covalent bond/antigen-mediated pathway for cell activation or cell death induction. The signal triggered through chemical modification of cell surface receptors or PTKs leads to activation of MAP family kinases, such as ERK, for cell activation. Through a not-yet-clarified pathway, chemical molecular modification also induces activation of JNK and p38 kinase in the MAP family, and c-Jun, which ultimately causes apoptotic cell death. The newly introduced alternative pathway of signal transduction that bypasses specific ligand (antigen)-receptor binding could also assist the antigen-mediated pathway for augmenting the immune function on the one hand, and disregulate the network of the immune system leading to production of immunological disorders/diseases on the other.
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