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

  • Kanji Yoshida
  • Tetsuya Taga
  • Mikiyoshi Saito
  • Atsushi Kumanogoh
  • Takashi Tanaka
  • Keiichi Ozono
  • Masahiro Nakayama
  • Tatsutoshi Nakahata
  • Nobuaki Yoshida
  • Tadamitsu Kishimoto
Chapter
Part of the Contemporary Immunology book series (CONTIM)

Abstract

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.

Keywords

Atrial Natriuretic Peptide Fetal Liver Primordial Germ Cell Mutant Embryo Target Disruption 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Kanji Yoshida
  • Tetsuya Taga
  • Mikiyoshi Saito
  • Atsushi Kumanogoh
  • Takashi Tanaka
  • Keiichi Ozono
  • Masahiro Nakayama
  • Tatsutoshi Nakahata
  • Nobuaki Yoshida
  • Tadamitsu Kishimoto

There are no affiliations available

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