Cellbound and soluble forms of ligands and receptors

The term 'soluble receptors' (SRs) is an apparent paradox. Originating from the field of hormone research, the terms 'receptors' and 'ligands' initially stood for features that are peculiar to the endocrine mode of intercellular communication. In this mode, the communicating cells play different roles; cells of the endocrine gland serve as the source of the message and the cells of the target tissue respond to it. Accordingly, the ligands and the receptors that participate in this communication also have distinct features, the ligand molecules serving solely to transfer the information and thus occurring only in a soluble, secreted form, and the receptors acting solely for receiving this information and thus, by definition, occurring solely in association with the target cell.

With the increasing knowledge of the cytokines and the ways in which they act, it became clear that in most cases transfer of molecular information does not occur, as in endocrine regulation, between cells that serve solely an effector or a target role. In fact, all nucleated cells serve both as producers of cytokines and as targets for their action. Nor is the transfer of molecular information restricted only to interaction between remote cells. Much of the action of cytokines occurs in close proximity to their site of formation, namely, in autocrine, juxtacrine and paracrine ways. The physical states and functional roles of receptor and ligand molecules may therefore be quite different from those that, prior to the era of cytokine research, were considered as definitive. Both receptors and ligands can occur in cell-bound as well as in soluble forms. Moreover, some cell-bound molecules have the ability to function at the same time both as receptors and as ligands. Their binding to receptors expressed on other cells results both in triggering of signaling by the latter receptors and in triggering of signals that they themselves produce (reversed signaling; illustrated in Figure 1(2)).

Another former distinction which we now view differently concerns the functional significance of the various regions in the receptor molecule. According to the initial concepts of the way in which receptors act, their extracellular domains appeared to serve merely a subsidiary role to that of the signaling intracellular domains. The discovery of the SRs highlighted the fact that recognition of the ligand by the extracellular domain can have some functional consequences that are independent of the function of other regions in the receptor. In a few cases, this independent role of the extracellular domain can be observed even when it is still cell bound. The extracellular domain of the type II interleukin 1 (IL-1) receptor, for example, has been shown to act as a 'decoy receptor'; that is to say, it serves solely as a means of restricting the availability of IL-1 to the other (type I) IL-1 receptor, thereby decreasing signaling by it. Another example, opposite in nature, is an apparent ability of the extracellular domain of CD120b (the p75 tumor nccrosis factor receptor, TNF-R) to assist binding of TNF to coexpressed CD120a molecules ('ligand passing'). However, most of our knowledge of such 'extracellular domain-specific' functions concerns SRs.

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