Receptors for the Four‐Helical Cytokines

Abstract

Cytokines belong to a family of proteins that coordinate the activity of the immune system and many other body functions. Most cytokines belong to a protein family exhibiting a four‐helical topology. Receptors for these cytokines belong to the immunoglobulin superfamily and are all type I transmembrane proteins. Within the cell, cytokines typically signal via the JAK–STAT‐signalling pathway and also via the Ras‐MAP‐kinase‐, Akt‐, PI3‐kinase and YAP pathways. Many cytokines form families, which are defined by common receptor subunits shared by the cytokine family members, thereby reducing the number of receptor complexes. Furthermore, this set‐up results in similar modes of signalling for the members of one cytokine family. Some cytokines with a four‐helical topology have been recognised as important therapeutic targets for the treatment of autoimmune diseases.

Key Concepts

  • Cytokines are small proteins of 100–200 amino acids, which belong to several different protein families.
  • Most, but not all, cytokines belong to the four‐helical class of cytokines.
  • Many cytokines can be grouped into families, which are defined by the usage of common receptor subunits and therefore share many signalling pathways.
  • Cytokine receptors also occur as soluble proteins, which can act as agonists and antagonists.
  • Cytokines and cytokine receptors are therapeutic targets for the treatment of autoimmune diseases.

Keywords: cytokine binding; immunoglobulin superfamily; JAK–STAT signalling; shedding; autoimmune disease

Figure 1. Cell surface receptor complex formation of cytokines. Binding of growth hormone (GH), granulocyte–macrophage colony‐stimulating factor (GM‐CSF), ciliary neurotrophic factor (CNTF) and IL‐12 to their cell surface receptors. (a) GH binds to a homodimer of the GH receptor. (b) GM‐CSF first binds to the GM‐CSF receptor. This complex then binds to the β subunit of the IL‐3 receptor. (c) CNTF first binds to the CNTF receptor. This complex thereupon associates with a heterodimer of gp130 and LIF receptor. (d) The heterodimeric cytokine IL‐12 consists of the four‐helical cytokine p35 and the soluble receptor p40. IL‐12 signals via a heterodimeric receptor complex of IL‐12Rβ1 and IL‐12Rβ2.
Figure 2. Signal transduction of cytokines. Dimerisation of signal‐transducing cytokine receptor subunits leads to Janus kinase (JAK) activation. The activated JAK phosphorylates the cytoplasmic portion of the cytokine receptor. This leads to signal transducer and activator of transcription (STAT) recruitment via phosphotyrosine, recognising Src homology‐2 (SH2) domains. Phosphorylated STAT factors dimerise and translocate to the cell nucleus where STAT factors act as transcription factors leading to the transcriptional activation of target genes. Additional signalling pathways are initiated via SHP2, MAPK and PI3K or via Src family kinases (SFK) and the yes‐associated protein (YAP) pathway.
Figure 3. Possible consequences of soluble receptor formation. (a) Inhibition of cytokine signalling by soluble receptors. Soluble receptors compete with membrane‐bound receptors for the ligand. A molar excess of soluble receptor leads to an inhibition of the cytokine response. (b) Activation of target cells by trans‐signalling via soluble cytokine receptors. Some cytokine receptors can bind their cognate ligands and thereafter bind to transducing subunits, thereby inducing signal transduction.
Figure 4. Modes of cytokine signalling. (a) In classic signalling, the cytokine binds to the membrane‐bound α‐receptor leading to the dimerisation of two signalling receptors (β‐receptors) and subsequent intracellular signalling. (b) In trans‐signalling, the cytokine binds to a soluble α‐receptor and the complex of cytokine and α‐receptor binds to two signalling β‐receptors leading to dimerisation and intracellular signalling. (c) In trans‐presentation, the cytokine bound to the α‐receptor of one cell is trans‐presented to a second cell, thereby engaging two signalling β‐receptors, leading to dimerisation and subsequent intracellular signalling.
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Rose‐John, Stefan(Apr 2017) Receptors for the Four‐Helical Cytokines. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000930.pub3]