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Cytokine Receptors

Overview

Cytokine receptors are receptors that bind cytokines. In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the redundancy and pleiotropy of cytokines are a consequence of their homologous receptors, many authorities are now of the opinion that a classification of cytokine receptors would be more clinically and experimentally useful.

Classification of cytokine receptors

Table 1. Cytokine receptor products

Type I Cytokine Receptors CSF2RA / CD116 CSF3R / CD114 EPOR
PRLR / Prolactin receptor    
Type II Cytokine Receptors IFNAR1 IFNAR2 IFNGR1
IFNGR2 IFNLR1 IL10RB
Immunoglobulin Receptors CSF1R IL-1R IL18R1
TNF Receptors TNFRSF1A TNFRSF1B TNFRSF4
TNFRSF6B TNFRSF8 TNFRSF9
TNFRSF10 TNFRSF10A TNFRSF10B
TNFRSF10C TNFRSF11A TNFRSF11B
TNFRSF12A TNFRSF13B TNFRSF13C
TNFRSF14 TNFRSF17 TNFRSF18
TNFRSF19 TNFRSF21 TNFRSF22
TNFRSF25    
Chemokines Receptors CCR1 CCR2 CCR3
CCR4 CCR5 CCR6
CCR7 CCR8 CCR9
CCR10 CCRL1 CCRL2
CX3CR1 CXCR1 CXCR2
CXCR3 CXCR4 CXCR5
CXCR6 CXCR7 XCR1
TGFβ Receptors TGFBR1 TGFBR2 TGFBR3

A classification of cytokine receptors based on their three-dimensional structure has been attempted.

  • Type I cytokine receptor

Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands. These receptors are also known under the name hemopoietin receptors, and share a common amino acid motif (WSXWS) in the extracellular portion adjacent to the cell membrane. Members of the type I cytokine receptor family comprise different chains, some of which are involved in ligand/cytokine interaction and others are involved in signal transduction.

There are some examples as followed:

Erythropoietin receptor The erythropoietin receptor (EpoR) is a protein that in humans is encoded by the EPOR gene. EpoR is a 52kDa peptide with a single carbohydrate chain resulting in an approximately 56-57 kDa protein found on the surface of EPO responding cells. It is a member of the cytokine receptor family. EpoR pre-exists as dimers which upon binding of a 30 kDa ligand erythropoietin (Epo), changes its homodimerized state. These conformational changes result in the autophosphorylation of Jak2 kinases that are pre-associated with the receptor (i.e., EpoR does not possess intrinsic kinase activity and depends on Jak2 activity). At present, the most well-established function of EpoR is to promote proliferation and rescue of erythroid (red blood cell) progenitors from apoptosis.
GM-CSF receptor The granulocyte-macrophage colony-stimulating factor receptor also known as CD116 (Cluster of Differentiation 116), is a receptor for granulocyte-macrophage colony-stimulating factor, which stimulates the production of white blood cells. The receptor is normally located on myeloblast, mature neutrophil, but not on any erythroid or megakaryocytic lineage cells. It is associated with Surfactant metabolism dysfunction type 4.
G-CSF receptor The granulocyte colony-stimulating factor receptor (G-CSF-R) also known as CD114 (Cluster of Differentiation 114) is a protein that in humans is encoded by the CSF3R gene. G-CSF-R is a cell-surface receptor for the granulocyte colony-stimulating factor (G-CSF). The G-CSF receptors belong to a family of cytokine receptors known as the hematopoietin receptor family.The granulocyte colony-stimulating factor receptor is present on precursor cells in the bone marrow, and, in response to stimulation by G-CSF, initiates cell proliferation and differentiation into mature neutrophilic granulocytes and macrophages.
Prolactin receptor The prolactin receptor (PRLR)—encoded by a gene on chromosome 5p13-14—interacts with prolactin as a transmembrane receptor. Thus it contains an extracellular region that binds prolactin, a transmembrane region, and a cytoplasmatic region. The PRLR also binds and is activated by growth hormone (GH) and human placental lactogen (hPL) in addition to prolactin.

Cytokine Receptors Figure 1. Dimeric states of Erythropoietin Receptor.

  • Type II cytokine receptor

Type II cytokine receptors are transmembrane proteins that are expressed on the surface of certain cells, which bind and respond to a select group of cytokines. These receptors are similar to type I cytokine receptors except they do not possess the signature sequence WSXWS that is characteristic of type I receptors. Typically type II cytokine receptors are heterodimers or multimers with a high and a low affinity component. Currently no complete structure of the extracellular domains of a type II cytokine receptor is available. These receptors are related predominantly by sequence similarities in their extracellular portions that are composed of tandem Ig-like domains. The intracellular domain of type II cytokine receptors is typically associated with a tyrosine kinase belonging to the Janus kinase (JAK) family.

Interferon-alpha/beta receptor The interferon-α/β receptor (IFNAR) is a virtually ubiquitous membrane receptor which binds endogenous type I interferon (IFN) cytokines. Endogenous human type I IFNs include many subtypes, such as interferons-α, -β, -ε, -κ, -ω, and -ζ. Type I IFN receptor forms a ternary complex, composed of its two subunits IFNAR1 and IFNAR2, and a type I IFN ligand. Ligand binding to either subunit is required for and precedes dimerization and activation of the receptor. Each subunit of IFNAR contains an N-terminal ligand binding domain (with two or four fibronectin type II-like subdomains, for IFNAR2 and IFNAR1, respectively), a transmembrane (TM) domain, and a cytoplasmic domain.
Interferon-gamma receptor The interferon-gamma receptor (IFNGR) is a receptor that binds interferon-γ, the sole member of interferon type II. The human interferon-gamma receptor complex consists the heterodimer of two chains: IFNGR1 and IFNGR2. In unstimulated cells, these subunits are not preassociated with each other but rather associating through their intracellular domains with inactive forms of specific Janus family kinases (Jak1 and Jak2). Jak1 and Jak2 constitutively associate with IFNGR1 and IFNGR2, respectively.

Cytokine Receptors Figure 2. Structure of the IFNGR1 protein.

  • Immunoglobulin superfamily

The immunoglobulin superfamily (IgSF) is a large protein superfamily of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on shared structural features with immunoglobulins (also known as antibodies); they all possess a domain known as an immunoglobulin domain or fold. Members of the IgSF include cell surface antigen receptors, co-receptors and co-stimulatory molecules of the immune system, molecules involved in antigen presentation to lymphocytes, cell adhesion molecules, certain cytokine receptors and intracellular muscle proteins. They are commonly associated with roles in the immune system.

Interleukin-1 receptor Interleukin-1 receptor (IL-1R) is a cytokine receptor which binds interleukin 1. Two forms of the receptor exist. The type I receptor is primarily responsible for transmitting the inflammatory effects of interleukin-1 (IL-1) while type II receptors may act as a suppressor of IL-1 activity by competing for IL-1 binding. Also opposing the effects of IL-1 is the IL-1 receptor antagonist (IL-1RA). The IL-1 receptor accessory protein (IL1RAP) is a transmembrane protein that interacts with IL-1R and is required for IL-1 signal transduction.
Colony stimulating factor 1 receptor Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), is a cell-surface protein encoded, in humans, by the CSF1R gene (known also as c-FMS). It is a receptor for a cytokine called colony stimulating factor 1.
Interleukin-18 receptor The interleukin-18 receptor (IL-18R) is an interleukin receptor of the immunoglobulin superfamily. IL-18R is a heteromeric complex of alpha- and beta-chains encoded by the genes IL18R1 and IL18RAP respectively. Endometrial IL-18 receptor mRNA and the ratio of IL-18 binding protein to interleukin 18 are significantly increased in adenomyosis patients in comparison to normal people, indicating a role in its pathogenesis.

Cytokine Receptors Figure 3. Structure of protein CSF1R.

  • TNF receptor superfamily

The tumor necrosis factor receptor superfamily (TNFRSF) is a protein superfamily of cytokine receptors characterized by the ability to bind tumor necrosis factors (TNFs) via an extracellular cysteine-rich domain. With the exception of nerve growth factor (NGF), all TNFs are homologous to the archetypal TNF-alpha. In their active form, the majority of TNF receptors form trimeric complexes in the plasma membrane. Accordingly, most TNF receptors contain transmembrane domains (TMDs), although some can be cleaved into soluble forms (e.g. TNFR1), and some lack a TMD entirely (e.g. DcR3).

There are some examples as followed:

Tumor necrosis factor receptor 1 Tumor necrosis factor receptor 1 (TNFR1), also known as tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and CD120a, is a ubiquitous membrane receptor that binds tumor necrosis factor-alpha (TNFα). This receptor can activate the transcription factor NF-κB, mediate apoptosis, and function as a regulator of inflammation. Antiapoptotic protein BCL2-associated athanogene 4 (BAG4/SODD) and adaptor proteins TRADD and TRAF2 have been shown to interact with this receptor, and thus play regulatory roles in the signal transduction mediated by the receptor.
Lymphotoxin beta receptor Lymphotoxin beta receptor (LTBR), also known as tumor necrosis factor receptor superfamily member 3 (TNFRSF3), is a cell surface receptor for lymphotoxin involved in apoptosis and cytokine release. The protein specifically binds the lymphotoxin membrane form (a complex of lymphotoxin-alpha and lymphtoxin-beta). The encoded protein and its ligand play a role in the development and organization of lymphoid tissue and transformed cells.
B-cell activating factor receptor B-cell activating factor (BAFF) enhances B-cell survival in vitro and is a regulator of the peripheral B-cell population. The protein encoded by this gene is a receptor for BAFF and is a type III transmembrane protein containing a single extracellular phenylalanine-rich domain. It is thought that this receptor is the principal receptor required for BAFF-mediated mature B-cell survival.

  • Chemokine receptor

Chemokine receptors are divided into different families, CXC chemokine receptors, CC chemokine receptors, CX3C chemokine receptors and XC chemokine receptors that correspond to the 4 distinct subfamilies of chemokines they bind. Four families of chemokine receptors differ in spacing of cysteine residues near N-terminal of the receptor. Learn more information about chemokines and chemokine receptors.

CXC chemokine receptors CXC chemokine receptors are integral membrane proteins that specifically bind and respond to cytokines of the CXC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins, since they span the cell membrane seven times. There are currently seven known CXC chemokine receptors in mammals, named CXCR1 through CXCR7.
CC chemokine receptors CC chemokine receptors (or beta chemokine receptors) are integral membrane proteins that specifically bind and respond to cytokines of the CC chemokine family. They represent one subfamily of chemokine receptors, a large family of G protein-linked receptors that are known as seven transmembrane (7-TM) proteins since they span the cell membrane seven times. To date, ten true members of the CC chemokine receptor subfamily have been described. These are named CCR1 to CCR10 according to the IUIS/WHO subcommittee on chemokine nomenclature.
C chemokine receptors The "C" sub-family of chemokine receptors contains only one member: XCR1, the receptor for XCL1 and XCL2 (or lymphotactin-1 and -2). XCR1 is also known as GPR5. XCL1 is expressed by medullary thymic epithelial T cells (mTECs) while XCR1 is expressed by thymic dendritic cells (tDCs). This communication helps with the destruction of cells that are not self-tolerant.
CX3C chemokine receptors CX3C chemokine receptor 1 (CX3CR1) also known as the fractalkine receptor or G-protein coupled receptor 13 (GPR13) is a protein that in humans is encoded by the CX3CR1 gene. As the name suggests, this receptor binds the chemokine CX3CL1 (also called neurotactin or fractalkine).

  • TGF beta receptor

Transforming growth factor beta (TGFβ) receptors are single pass serine/threonine kinase receptors. They exist in several different isoforms that can be homo- or heterodimeric. The number of characterized ligands in the TGFβ superfamily far exceeds the number of known receptors, suggesting the promiscuity that exists between the ligand and receptor interactions.

Transforming growth factor beta receptor I Transforming growth factor beta receptor I (activin A receptor type II-like kinase, 53kDa) is a membrane-bound receptor protein for the TGF beta superfamily of signaling ligands. TGFBR1 is its human gene. The protein encoded by this gene forms a heteromeric complex with type II TGF-β receptors when bound to TGF-β, transducing the TGF-β signal from the cell surface to the cytoplasm. The encoded protein is a serine/threonine protein kinase. Mutations in this gene have been associated with Loeys–Dietz aortic aneurysm syndrome (LDS, LDAS).
Transforming growth factor beta receptor II Transforming growth factor beta receptor II (70/80kDa) is a TGF beta receptor. TGFBR2 is its human gene. It is a tumor suppressor gene. This gene encodes a member of the serine/threonine protein kinase family and the TGFB receptor subfamily. The encoded protein is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with another receptor protein, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of a subset of genes are related to cell proliferation.

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