The tripartite CNTF receptor complex: activation and signaling involves components shared with other cytokines

Abstract

Recent efforts to understand the mechanism of action of CNTF have led to the identification of a three-component receptor complex for CNTF. The distributions of these receptor components explain the known target cell specificity of CNTF, and have also helped identify new and unexpected targets of CNTF action. In addition to including a CNTF-specific component, known as CNTFR alpha, the CNTF receptor complex utilizes two receptor components, gp130 and LIFR beta, that are shared with members of a family of broadly acting cytokines, including leukemia inhibitory factor (LIF) and interleukin-6 (IL6). The finding that the CNTF receptor complex shares components with this family of cytokines has led to the realization that CNTF should also be considered a cytokine--but one that differs from its relatives in that its actions are largely limited to cells of the nervous system due to the restricted expression of one of its receptor components, CNTFR alpha. CNTFR alpha does not play a direct role in signaling, but instead forms a complex with CNTF that promotes its binding to the signal transducing "beta" receptor components, gp130 and LIFR beta. Thus CNTF utilizes identical signal transducing receptor components in neurons that its relatives use on nonneuronal cells to elicit strikingly dissimilar responses, indicating that different cells interpret the same cell surface signal in dramatically different ways. The three CNTF receptor components are initially unassociated on the cell surface, and are brought together in step-wise fashion upon CNTF binding. CNTF first binds to CNTFR alpha, then recruits gp130, and finally complexes with LIFR beta. It is this last step in complex formation, involving heterodimerization between "beta" components, that activates intracellular signaling. Signal initiation is due to activation of members of a family of cytoplasmic tyrosine kinase, known as the Jak/Tyk kinases, which are preassociated with the beta components in an inactive state and then become activated upon beta component dimerization; the Jak/Tyk kinases, in turn, activate a variety of intracellular signaling molecules, such as members of the STAT family of DNA binding transcriptional activators. A detailed understanding of the mechanism of activation of the CNTF receptor complex has led to the realization that all members of the CNTF family of cytokines activate signaling in much the same way, by inducing either homo- or heterodimerization of beta receptor components and thus activation of the preassociated Jak/Tyk kinases; this mode of receptor activation may prove to be more generally applicable to all cytokine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)