Cytokines act on their target cells by binding specific membrane receptors. Many cell functions are regulated by members of the cytokine receptor superfamily. Signaling by cytokine receptors depends upon their association with the Janus kinases (JAKs), which couple ligand binding to tyrosine phosphorylation of signaling proteins recruited to cytokine receptor complex. Among these signaling proteins are unique family of transcription factors named the signal transducers and activators of transcription (STATs). The receptors and their corresponding cytokines have been divided into several families based on their structure and activities, including:
A classification of cytokine receptors based on details of their structural organization has been attempted.
|Types of Cytokine Receptors||Examples||Structure|
|Type I Cytokine Receptors||
Certain conserved motifs in their extracellular amino-acid domain. (Figure 1. NMR structure of the ligand binding domain of the common beta chain in the GM-CSF, IL-3 and IL-5 receptors). Connected to Janus kinase (JAK) family of tyrosine kinases
|Type II Cytokine Receptors||
Certain conserved motifs in their extracellular amino-acid domain. (Figure 2. NMR structure of the interferon binding ectodomain of the human interferon receptor). Connected to Janus kinase (JAK) family of tyrosine kinases
Common motif of seven transmembrane helix. (Figure 3. CXCR3 Binding Chemokine IP-10 / CXCL10). Couple to G-protein for signal transduction
|Tumor Necrosis Factor Receptor (TNFR) Superfamily||
Cysteine-rich common ectodomain of TNFR. (Figure 4. Crystal structure of the soluble human 55 kd TNF receptor and human TNF-beta complex).
Serine/threonine protein kinase. (Figure 5. Transforming Growth Factor Beta type II receptor ligand binding domain).
|Immunoglobulin (Ig) Superfamily||
Share structural homology with immunoglobulins (antibodies). (Figure 6. Structural determinants of the NHERF interaction with beta2-AR and PDGFR).
Type I cytokine receptors have certain conserved motifs in their extracellular amino-acid domain, and lack an intrinsic protein tyrosine kinase activity. This family includes receptors for IL2 (beta-subunit), IL3, IL4, IL5, IL6, IL7, IL9, IL11, IL12, GM-CSF, G-CSF, Epo, LIF, CNTF, and also the receptors for Thrombopoietin (TPO), Prolactin, and Growth hormone. Type I cytokine receptor family is subdivided into three subsets on the basis of the ability of family members to form complexes with one of three different types of receptor signaling components (gp130, common beta, and common gamma - the gamma-chain of the IL2 receptor).
The conserved extracellular domain of type I cytokine receptors has a length of approximately 200 amino acids, which contains four positionally conserved cysteine residues in the amino-terminal region and a Trp-Ser-X-Trp-Ser motif (WSXWS motif) located proximal to the transmembrane domain. The four cysteines appear to be critical to the maintenance of the structural and functional integrity of the receptors. The WSXWS consensus sequence is thought to serve as a recognition site for functional protein-protein interaction of cytokine receptors.
Type II cytokine receptors are multimeric receptors composed of heterologous subunits, and are receptors mainly for interferons. This family includes receptors for IFN-alpha, IFN-beta, IFN-gamma, IL10, IL22, and tissue factor. The extracellular domains of type II cytokine receptors share structural similarities in their ligand-binding domain. Several conserved intracellular sequence motifs have been described, which probably function as binding sites for the intracellular effector proteins JAK and STAT proteins.
Chemokine receptors are G protein-coupled receptors with 7 transmembrane structure and couple to G-protein for signal transduction. Chemokine receptors are divided into different families: CC chemokine receptors, CXC chemokine receptors, CX3C chemokine receptors, and XC chemokine receptor (XCR1).
Tumor necrosis factor receptor (TNFR) family members share a cysteine-rich domain (CRD) formed of three disulfide bonds surrounding a core motif of CXXCXXC creating an elongated molecule. TNFR is associated with procaspases through adapter proteins (FADD, TRADD, etc.) that can cleave other inactive procaspases and trigger the caspase cascade, irreversibly committing the cell to apoptosis.
TGF-beta receptors are single pass serine/threonine kinase receptors. TGF-beta receptors include TGFBR1, TGFBR2, and TGFBR3 which can be distinguished by their structural and functional properties.
Cytokine receptors belonging to the immunoglobulin (Ig) superfamily include IL1R (type I and II), PDGFR, SCFR, CSF-1R, etc.
Cytokine receptors contain one to three chains, one or more of which generally have limited similarity in the membrane-proximal region (often referred to as box1/box2 motifs). According to the nomenclature the ligand-binding subunit of a receptor is referred to as the alpha chain. Other signal transducing subunits are named beta chains, or gamma chains. All cytokine receptors are associated with one or more members of JAKs, which couple ligand binding to tyrosine phosphorylation of various signaling proteins (STATs) recruited to the receptor complex.
Molecular cloning of cytokine receptors and subsequent structure–function studies has revealed that unlike growth factor receptors, cytokine receptors are devoid of catalytic activity. Nevertheless, interaction of a cytokine with its receptor rapidly induces tyrosine phosphorylation of the receptor and a variety of cellular proteins, suggesting that these receptors transmit their signals through cellular tyrosine kinases. During the past 10–15 years, a large amount of experimental data have accumulated to indicate that most cytokines transmit their signals via a distinct family of tyrosine kinases termed Janus kinases or JAKs.
Cytokine receptors activate many signaling pathways generally by means of phosphotyrosine residues, which are recognized by SH2 domains on the signaling molecules. The STATs contain a carboxy-terminal SH2 domain, an SH3-like domain and several conserved amino-terminal regions, and a conserved region in the middle of the protein that binds DNA. Tyrosine phosphorylation of a carboxy-terminal site mediates homo- or heterodimerization through the SH2 domains, triggering movement to the nucleus and DNA binding.
A native un-liganded receptor in complex with a JAK is in a catalytically inactive latent state. Receptor dimerization/oligomerization due to ligand binding results in the juxtapositioning of the JAKs, which are in the vicinity through either homo- or heterodimeric interactions. The recruitment of JAKs appears to result in their phosphorylation, either via autophosphorylation and/or cross phosphorylation by other JAKs or via other families of tyrosine kinases. This activation is presumed to result in increased JAK activity. Activated JAKs then phosphorylate receptors on target tyrosine sites. The phosphotyrosine sites on the receptors can then serve as docking sites that allow the binding of other SH2-domain containing signaling molecules such as STATs, Src-kinases, protein phosphatases and other adaptor signaling proteins such as Shc, Grb2 and phosphatidylinositol 3-kinase (PI3K).
Cytokines and cytokine receptors regulate many important biological processes, including development, haematopoesis, inflammation, immune responses and tissue repair. The roles of cytokine receptors and cytokine receptor signaling through Jak-Stat have attracted considerable interest as a potential source of therapeutic targets for the management of complex human diseases.
Hperactivating mutations affecting type I cytokine receptor signaling pathway are found associated with several myeloproliferative diseases. On the other hand, inappropriate activation of type I cytokine receptor signaling appears to be a hallmark of a range of malignancies, including leukemias and lymphomas. Studies also indicated that mutations in specific type I cytokine receptors was associated with a range of haematological defects. Specifically, defects in signaling by members of the IL-2 receptor family cause the majority of cases of severe combined immune deficiency (SCID). In addition, defects in type II receptor signaling components produce more subtle and specific immune deficiencies. Several other cytokine receptor types are also involve in a range of a range of autoimmune disorders. Moreover, several different inflammatory diseases have been shown to be due to abnormalities in cytokine receptor signaling pathways.