Myocardial, Hematological, and Placental Disorders Caused by Targeted Disruption of gp130, A Common Signal Transducer for IL-6 Family of Cytokines

Growth and differentiation of cells during development of organs are precisely coordinated by various membrane-anchored and soluble factors, the latter of which include so-called cytokines. Cytokine signals are mediated through specific receptor complexes expressed on target cells. Most of the cytokine receptor components, in particular those involved in hernatopoietic cell regulation, belong to a large group of proteins called the cytokine receptor family (1). A notable finding is that receptor complexes from this family are usually composed of a ligand-specific receptor chain and a signal transducer common to multiple cytokines (2,3). gp130 was initially identified as a signal transducing receptor component that associates with the interleukin-6 receptor (IL-6R) when the receptor binds with IL-6 (4,5). It has been shown that gp130 is also utilized as a critical signal transducing component in the receptor complexes for IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1) (6–10). The discovery of this shared signal transducer, gp 130, helps to explain how these different cytokines can mediate overlapping biological functions (11). This system of utilizing multichain components with a shared signal transducer is not confined to the IL-6-family of cytokines, but is also applicable to two other families of cytokines: granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, and IL-5, all of which share a common chain referred to as βc (12); and IL-2, IL-4, IL-7, IL-9, and IL-15 which share the IL-2Rγ chain, γc (13–15). A general first step in the process of signaling by members of the cytokine receptor family is believed to be the ligand-induced dimerization of receptor components. In the case of the IL-6-family of cytokines, IL-6-binding to IL-6R induces homodimerization of gp130 (16), whereas stimulation by LIF, OSM, CNTF, and CT-1 leads to heterodimerization of gp130 with a closely related protein, LIFR (7,10,17). OSM is suggested to signal also through a different type of heterodimer composed of OSM-specific receptor and gp130 (18,19). From the close structural similarity of IL-6R and IL-11R, the gp130 homodimer could be a candidate complex for IL-11 signaling (20). Homo- or heterodimerization of gp130 triggers the activation of JAK1, JAK2, and TYK2, all of which are in the JAK-family of cytoplasmic tyrosine kinases and are associated with gp130 (21–23). This leads to the subsequent tyrosine-phosphorylation and acquisition of DNA-binding capability of a latent cytoplasmic transcription factor, APRF/STAT3 (for acute phase response factor or signal transducer and activator of transcription 3) (24–26). It has recently been shown that phosphorylation of a serine residue in STAT3 is important for the full activation of STAT3 (27–29). The Ras/MAPK cascade has been revealed to be activated following gp130-stimulation (30–32). One of the targets of MAPK is NF-IL6, which was demonstrated to be activated on threonine phosphorylation by MAPK (33). A precise mechanism which links the gp130-dimerization and MAPK activation remains to be elucidated.