gp130 and the IL-6 family of cytokines: signaling mechanisms and thrombopoietic activities

Abstract

gp130 is a common signal transducing component of the functional receptor complexes for the interleukin (IL)-6 family of cytokines, ie, IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1. These cytokines exhibit pleiotropic biological activities in, for instance, immune, hematopoietic, and neural systems, and function in a redundant manner owing to the shared usage of gp130. Thrombopoiesis is regulated by a variety of polypeptide factors including some from the IL-6 family. A polypeptide that has the most potent thrombopoietic activity among the thus far identified molecules is thrombopoietin (TPO). TPO exerts its biological functions through its cognate receptor, c-MPL, that interestingly is classified into the hematopoietic cytokine receptor family in which gp130 also belongs. Although each member of the IL-6 family as well as TPO signals through the distinct receptor complex, the underlying signaling mechanism is similar in each case: the first event after cytokine stimulation is dimerization of a respective set of receptor components, and activation of receptor-associated tyrosine kinases in the janus kinase (JAK) family then follows. Activation of JAK kinases is the pivotal step to initiate downstream cytoplasmic signaling cascades involving signal transducer and activator of transcription transcription factors and mitogen activated protein kinase. In this article, we focus on gp130-mediated cytokine signal transduction by comparing that mediated by c-MPL.