Cytokine Receptors (Hematopoetin Receptor Family)

A broad array of molecules can be functionally termed cytokines. These secreted or membrane-bound regulatory factors control myriad developmental, metabolic and host defense processes in cells that display the correct assortment of surface receptors. Cytokine ligands and cellular receptors then form specific binding complexes that trigger intracellular signaling cascades to recast the fate of the cell. The rules of engagement between cytokines and receptors are highly structural in nature; cytokine and receptor families have distinct domain architectures that are employed in specific and highly conserved three-dimensional interactions.

The largest and most divergent family of cytokines are the hematopoietic factors that comprise around 50 distinct lymphokines, growth hormones, hemopoietins, neuropoietins and interleukins. In spite of minimal sequence homology, these hematopoietic cytokines have a singular four-α-helix protein fold that has been evolutionarily honed to interact with approximately 45 receptors that sport a distinctive pair of fibronectin-type-3 (Fn3) modules. As a number of receptor crystal structures reveal, these Fn3 modules fold as β-sheet sandwiches (reminiscent of Ig domains) with a characteristic “bent” hinge that forms a loop-rich binding site for their helical cytokine ligands. This conserved protein-protein interaction mode is capable of granting both high specificity or perplexing promiscuity to ligand binding, since both dedicated (or ‘private’) and shared receptors are found in the hematopoietic family. The latter type includes critical molecules such as Rγc (a common chain in IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptor complexes), Rβc (likewise for IL-3, IL5 and GMCSF), gp130 for the IL-6-like cytokine clan, and IL-10R2 for the IL-10-like factors.

Though hematopoietic cytokines all share a common fold topology, sequence divergence has given rise to differences in the length and packing of their core α-helices, variations in loop geometry and extracore adornments such as short β-strands or α-helices nestled against the α-helical bundle core. These divergent architectural themes underlie the current classification of hematopoietic cytokines into three types, Short-chain (like the aforementioned ligands of Rγc and Rβc), Long-chain (comprising the IL-6-like cytokines, growth hormones, EPO and TPO) and Interferon-like (IFNs-α/β/γ and the IL-10-like cytokines). This structural division of cytokine ligands mirrors an evolutionary split of their respective receptors into Class 1 (or classically hematopoietic) Receptors for either Short- or Long-chain cytokines, and Class 2 (or Interferon-like) Receptors for Interferon-like cytokines.

Structural investigations have uncovered a greater complexity of ligand/receptor interactions than was first revealed in the paradigmatic framework of the growth hormone (GH) receptor complex where the cytokine was cradled between two receptor subunits that formed a face-to-face dimer. The majority of Class 1 and 2 hematopoietic cytokines utilize this scheme, driving association of a receptor homodimer (like GH, PRL, EPO and TPO) or heterodimer (all of the Short-chain and Interferon-like factors) to create an active signaling complex. The IL-6-like cytokines of the Class 1, Long-chain group, including IL-6, IL-11, IL-12, IL-23, IL-27, IL-31, CLC, CNTF, CT-1, GCSF, Leptin, LIF and OSM, have evolved an additional (non-GH-like) receptor-binding epitope that captures an N-terminal Ig domain of their second critical hematopoietic receptor signaling chain. This more elaborate choreography of gp130-like receptors assembling around IL-6-like cytokines is reflected in the subunit composition of the particular receptor complexes (see Table). However, exceptions exist in the form of three membrane-tethered Short-chain cytokines, namely FLT3L, MCSF and SCF, that are obligate dimers that appear to have escaped the confines of the hematopoietic cytokine receptor family and bind to three tyrosine-kinase receptors of the PDGFR class, FLT-3, FMS and KIT, respectively.

The hematopoietic cytokine/receptor system, which funnels its signals through conserved JAK/STAT intracellular pathways, is arguably the key regulator of the developmental fates and functional roles of blood cell types. As such, this system is critical in helping marshall and shape effective immune responses to pathogen attack. Dysregulation of this molecular network by mutation or pathogen deception, can contribute to a variety of human immuno-deficiencies or cancers. Nevertheless, efforts are underway to develop small molecule drugs that either augment or suppress hematopoietic receptor signaling by targeting critical points of interaction between cytokines and their receptors, or receptors and intracellular effectors.

 

The Tables below contain accepted modulators and additional information.

 

Class 1 (Short Chain) Hematopoietin Receptor Family

Receptor Fora IL-2 IL-3 IL-4
IL-5 IL-7
Currently Accepted Name IL-2 Receptor IL-3 Receptor IL-4 Receptor IL-5 Receptor IL-7 Receptor
Alternative Name TCGF  Multi-CSF
MCGF
BCGF
BSF-1
EDF PreBCGF 
Subunit Composition IL2Rα (I0779)/
IL2Rβ (I0904)/
Rγc (I1029)
IL3Rα/
Rβc
IL4R/
Rγc
IL5Rα/
Rβc
IL7R2/
Rγc
Selective Agonistsa,b IL-2 (I2644I7908 (h), I0523 (m))
IL-4 (I4269 (h), I1020 (m), I3650 (r))
IL-7 (I5896 (h), I4892 (m))
IL-15 (I8648)
IL-3 (I1646I7389 (h), I4144 (m)) IL-4 (I4269 (h), I1020 (m), I3650 (r)) IL-5 (I5273 (h), I1145 (m)) IL-7 (I5896 (h), I4892 (m))
Signal Transduction Mechanisms JAK/STAT
lyn
lck
JAK/STAT JAK/STAT
IRS-1
JAK/STAT
4PS
lyn
JAK/STAT
Radioligands of Choice [125I]-IL-2 [125I]-IL-3 [125I]-IL-4 [125I]-IL-5 [125I]-IL-7
Tissue Expression Thymus Activated T-cells
Mast cells
Eosinophils
Th2-cells
NK-T cells
Mast cells
T-cells
Mast cells
Bone marrow stromal cells
T-cells
Physiological Function Hematopoiesis
Proliferation of T- and B-cells
Growth/proliferation of immune cells Proliferation/development of Th2 cells
B-cell proliferation
Activation of monocytes-macrophages
Growth/differentiation of B-cells and eosinophils Early B- and T-cell development
Disease Relevance Therapeutic for many cancers Myeloid leukemias Allergy
Asthma
Allergy
Asthma
Psoriasis

 

Receptor Fora IL-9 IL-13 IL-15 IL-21
Currently
Accepted
Name
IL-9 Receptor IL-13 Receptor IL-15 Receptor IL-21 Receptor
Alternative
Name
       
Subunit
Composition
IL9R/
Rγc
IL13Rα1/
IL4Rα
IL13Rα2=decoy
IL15Rα/
IL2Rβ/
Rγc
IL21R/
Rγc
Selective
Agonistsa,b
IL-9 (I3394 (h), I3269 (m)) IL-13 (I1771 (h), I1896 (m))
IL-7 (I5896 (h), I4892 (m))
IL-15 (I8648)
IL-15 (I8648)
IL-2 (I2644I7908)
IL-4 (I4269)
IL-7 (I5896)
IL-21
Signal
Transduction
Mechanisms
JAK/STAT JAK/STAT
lyn
lck
JAK/STAT JAK/STAT
Radioligands of
Choice
[125I]-IL-9 [125I]-IL-13 [125I]-IL-15 [125I]-IL-21
Tissue
Expression
Th2-cells Activated Th2 cells Placenta
Skeletal muscle
Activated CD4+ T-cells
Physiological
Function
Eosinophil differentiation
Mast cell proliferation
B-cell maturation/differentiation
Downregulates macrophages
T cell stimulation NK cell proliferation/maturation
B- and T-cell function
Inhibition of dendritic cells
Disease
Relevance
Asthma Asthma Arthritis Psoriasis

 

Receptor Fora GMCSF TSLP FLT3L MCSF SCF
Currently
Accepted
Name
GMCSF Receptor TSLP Receptor FLT3/FLK2 RTK c-FMS RTK c-KIT RTK
Alternative
Name
CSF2     CSF-1 MGF
Steel
Subunit
Composition
GMCSFRα/
Rβc
TSLPR/
IL7Rα
(FLT3)2 (FMS)2 (KIT)2
Selective
Agonistsa,b
GMCSF (G5035) TSLP
(IL-7)
Not Known Not Known
Not Known
Signal
Transduction
Mechanisms
JAK/STAT JAK/STAT Tyrosine Kinase Tyrosine Kinase Tyrosine Kinase
Radioligands of
Choice
[125I]-GMCSF [125I]-TSLP [125I]-FLT3L [125I]-MCSF [125I]-SCF
Tissue
Expression
Immune cells Spleen
Thymus
Kidney
Lung
Bone marrow
Immune cells Immune cells Immune cells
Physiological
Function
Hemopoietic progenitor growth/differentiation Myeloid stimulation
Dendritic cell and B-cell development
Stem cell growth factor Stem cell growth factor
Macrophage development
Immune defense
Bone metabolism
Stem cell growth factor
Mast cell development
Disease
Relevance
Therapeutic myeloid reconstitution Not Known Leukemia Leukemia Mast cell leukemia
Piebaldism
Gastrointestinal stromal tumor

 

 

Class 1 (Long Chain) Hematopoietin Receptor Family

Receptor For EPO TPO GH* PRL CLC CNTF
Currently Accepted Name EPO Receptor (E0643) TPO Receptor GH Receptor PRL Receptor CLF and CNTF Receptor CNTF Receptor
Alternative Name   MegCSF
MGDF
MPL ligand
Somatotropin Placental lactogen
BSF3
NNT1
 
Subunit Composition (EPOR)2 (TPOR)2 (GHR)2 (PRLR)2 CLF/NR6 for secretion
CNTFRα/gp130/LIFR
CNTFRα/gp130/LIFR
Selective Agonistsa,b EPO (E5627) TPO (T1568) GH/CS
PRL (L4021)
PRL (L4021)
GH/CS
CLC
CNTF (C3710)
LIF (L5283)
OSM (O9635)
CT-1
IL-6 (I1395, I3268)
IL-11 (I2406)
CNTF (C3710)
Signal Transduction Mechanisms JAK/STAT JAK/STAT JAK/STAT JAK/STAT JAK/STAT JAK/STAT
Radioligands of Choice [125I]-EPO [125I]-TPO [125I]-GH [125I]-PRL [125I]-CLC
[125I]-CNTF
[125I]-LIF
[125I]-LIF
[125I]-OSM
[125I]-CNTF
[125I]-LIF
[125I]-OSM
Tissue Expression Kidney
Liver
Liver Pituitary gland Placenta Lymph nodes
Spleen
PBLs
Bone marrow
Fetal liver
Central nervous sytem
Physiological Function Regulator of erythropoiesis Regulator of thrombopoiesis
Megakaryocyte development
Platelets
Growth control
Differentiation/proliferation of myoblasts
Promotes lactation by mammary gland B-cell stimulation
Neuronal regeneration
Neuronal regeneration
Disease Relevance Therapeutic for treatment of anemia Therapeutic for platelet reconstitution
Thrombocythemia
Dwarfism Not Known
Not Known Treatment for obesity
Amyotrophic lateral sclerosis

 

Receptor For CT-1 GCSF Leptin LIF OSM IL-6
Currently Accepted Name CNTF Receptor GCSF Receptor Leptin Receptor LIF Receptor LIF Receptor and OSM Receptor IL-6 Receptor (I5771
Alternative Name   CSF3
pluripoietin
Obese
OB
HILDA   IFN-β2
BSF2
Subunit Composition CNTFRα/gp130/LIFR (GCSFR)2 (LepR)2 gp130/LIFR gp130/LIFR
gp130/OSMR
IL6Rα/(gp130)2
Selective Agonistsa,b CT-1
LIF (L5283)
OSM (O9635)
CNTF (C3710)
IL-6 (I1395, I3268)
IL-11 (I2406)
GCSF (G0407) Leptin (L4146) LIF (L5283)
OSM (O9635)
IL-6 (I1395)
CT
IL-11 (I2406)
CNTF (C3710)
LIF (L5283)
OSM (O9635)
CT
IL-6 (I1395)
IL-11 (I2406)
CNTF (C3710)
IL-6 (I1395)
(OSM (O9635)
LIF (L5283)
IL-11 (I2406)
CNTF (C3710)
CT)
Signal Transduction Mechanisms JAK/STAT JAK/STAT
SH-PTPase
JAK/STAT JAK/STAT JAK/STAT JAK/STAT
Radioligands of Choice [125]-CT-1
[125I]-LIF
[125I]-OSM
[125I]-GCSF [125I]-Leptin [125I]-LIF [125I]-LIF
[125I]-OSM
[125I]-IL-6
[125I]-OSM
Tissue Expression Heart
Skeletal muscle
Prostate
Liver
Immune cells Adipocytes
Stem cells
Immune cells Activated leukocytes Immune cells
Physiological Function Cardiac myocte development Regulates granulocyte proliferation/maturation Early hematopoiesis
Regulation of obesity and metabolism
Bone development
Hematopoietic, neuronal and endothelial cell development Liver development
Hematopoiesis regulation
Proinflammatory
Bone resorption control
Hematopoiesis regulation
Plasma cell development
Disease Relevance Not Known
Therapeutic against neutropenia Obesity Arthritis Not Known
Therapeutic for cancers

 

Receptor For IL-11 IL-12p35 IL-23p19 IL-27p28 IL-31
Currently Accepted Name IL-11 Receptor IL-12 Receptor  IL-23 Receptor IL-27 Receptor IL-31 Receptor
Alternative Name AGIF NKSF1
IL-12A
IL-23A TCCR
WSX-1
GLMRL
Subunit Composition IL11R/gp130 p40/IL12Rβ1/IL12Rβ2 p40/IL12Rβ1/IL23R EBI3/TCCR/gp130 IL-31R/OSMR
Selective Agonistsa,b IL-11 (I2406)
(OSM (O9635)
CT
IL-6 (I1395)
LIF (L5283)
CNTF (C3710)
IL-12p35/p40 (I2276) IL-23p19/p40 IL-27p28/EBI3 IL-31
Signal Transduction Mechanisms JAK/STAT JAK/STAT JAK/STAT JAK/STAT JAK/STAT
Radioligands of Choice [125I]-IL-11 [125I]-IL-12p35/p40 [125I]-IL-23p19/p40 [125I]-IL-27p29/EBI3 [125I]-IL-31
Tissue Expression Stromal cells Monocytes
T-cells
B-cells
Monocytes
Dendritic cells
T-cells
NK-cells
Monocytes
Dendritic cells
Activated Th2 cells
Physiological Function T-cell proliferation and regulation, stimulates platelet production Promotes Th1 immune response
NK cell cytotoxicity
Pro-inflammatory
Promotes Th1 immune response
IFN-γ inducer
Proliferation of memory and naïve T-cells
Promotes Th1 immune response
Proliferation of naïve CD4+ T-cells
Immune response
Disease Relevance Therapeutic for psoriasis Chronic inflammatory diseases Chronic inflammation Chronic inflammation Epithelial skin disorders
Asthma
Allergy

 

 

Cytokine Receptors - Class 2 Hematopoietin Receptor Family

Receptor For  IFN-α/β** IFN-γ IL-10 IL-19 IL-20
Currently Accepted Name IFN-α Receptor-2 IFN-γ Receptor-1 IL-10 Receptor-1 IL-20 Receptor IL-20 Receptor
Alternative Name     CSIF    
Subunit Composition IFNαR2/IFNαR1 IFNγR1/IFNsγR2 (IL10R1)2/( IL10R2)2 IL20R1/IL20R2 IL20R1/IL20R2
IL22R1/IL20R2
Selective Agonists a,b IFN-α** (I4401, I4276)
IFN-β (I4151)
IFN-γ (I1520, I3265) IL-10 (I9276) IL-20
IL-24
IL-26
IL-20
IL-19
IL-22
IL-24
IL-26
Signal Transduction Mechanisms JAK/STAT
PI3K
NFkB
MAPK
PRMT1
JAK/STAT
PI3K
MAPK
NFkB
JAK/STAT JAK/STAT JAK/STAT
Radioligands of Choice [125I]-IFN-α/β [125I]-IFN-γ [125I]-IL-10 [125I]-IL-19 [125I]-IL-20
Tissue Expression Dendritic cells Th1 cells Th2 cells, B cells Monocytes, B cells Immune cells
Physiological Function Immune response against viral infection, antiviral, antiproliferative Immune response, triggers cytokine release Immunosuppressive functions, blocking cytokine production Immune response Immune response
Disease Relevance Lupus, rheumatoid arthritis; treatment of Hepatitis-B and -C, multiple sclerosis Chronic inflammatory disease Asthma, allergy Chronic inflammatory skin disease (e.g. psoriasis) Psoriasis

 

Receptor For  IL-22 IL-24 IL-26 IL-28α/β*** IL-29
Currently Accepted Name IL-22 Receptor IL-22 Receptor IL-20 Receptor IL-28 Receptor IL-28 Receptor
Alternative Name IL-TIF MDA7
FISP
AK155 IFN-l2/l3 IFN-l1
Subunit Composition IL22R1/IL10R2
IL22bp=Decoy
IL22R1/IL20R2
IL20R1/IL20R2
IL20R1/IL10R2 IL28R1/IL10R2 IL28R1/IL10R2
Selective Agonists a,b IL-22
IL-20
IL-24
IL-19
IL-20
IL-26
IL-26
IL19
IL-20
IL-24
IL-28α/β
IL-29
IL-29
IL-28α/β
Signal Transduction Mechanisms JAK/STAT JAK/STAT JAK/STAT JAK/STAT JAK/STAT
Radioligands of Choice [125I]-IL-22 [125I]-IL-24 [125I]-IL-26 [125I]-IL-28α/β [125I]-IL-29
Tissue Expression T cells, mast cells, thymus, brain Immune cells, PBLs, melanocytes T-cells, monocytes, NK-cells, B-cells T-cells T-cells
Physiological Function Immune response Immune response, apoptosis-inducing in tumor cells Immune response Immune response, antiviral, antiprolliferative Immune response, antiviral, antiproliferative
Disease Relevance Allergy Melanoma Upregulated in T-cells by Herpesvirus infection, stimulation of cytotoxic activity of immune cells Not Known
Not Known

 

Footnotes

a) Product numbers refer to the human cytokine. For other species, please visit our website at www.sigma-aldrich.com and use our Product Search.

b) Agonists not in parentheses are primary agonists for the receptor.

* = GH and four closely related chorionic somatotropin homologs

** = IFNα,β,δ,ε,κ,τ,ω and limitin

*** = IL28α and IL28β are two closely related cytokines

 

Abbreviations

4PS: IL-4-induced phosphotyrosine substrate
AGIF: Adipogenesis inhibitory factor
BCGF: B cell growth factor
BSF: B cell stimulatory factor
CLC: Cardiotrophin like cytokine
CLF: Cytokine-like factor
CNTF: Ciliary neurotrophic factor
CS: Chorionic somatotropin
CSF: Colony stimulating factor
CSIF: Cytokine synthesis inhibitory factor) (CSIF).
CT: Cardiotrophin
EDF: Eosinophil differentiation factor
EPO: Erythropoietin
FISP: IL4 induced secreted protein
FLT-3: Fms-like tyrosine kinase 3
FLT3L: Fms-related tyrosine kinase 3 ligand)
FMS: formerly McDonough feline sarcoma viral (v-fms) oncogene homolog
GH: Growth Hormone
GHR: Growth hormone receptor
GMCSF: Granulocyte macrophage colony stimulating factor
GSCF: Granulocyte colony stimulating factor
IFN: Interferon
IL: Interleukin
IL-TIF: IL-10-related T-cell-derived inducible factor
IRS-1: Insulin receptor substrate-1
Jak: Janus kinase
KIT: V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
LIF: Leukemia inhibitory factor
Lck: Lymphocyte-specific protein tyrosine kinase
Lyn: V-yes-1 Yamaguchi sarcoma viral related oncogene homolog
MCSF: Macrophage colony stimulating factor
MDA7: Melanoma differentiation-associated protein 7
MGDF: megakaryocyte growth and development factor
MGF: Mast cell growth factor
NKSF1: NK cell stimulatory factor chain 1
NNT1: Novel neurotrophin 1
OSM: Oncostatin M
PBLs: Peripheral blood leukocytes
PDGF: Platelet-derived growth factor
PRL: Prolactin
RTK: Protein tyrosine kinase
SCF: Stem cell growth factor
SH-PTPase: Src homology domain 2-containing protein tyrosine phosphatase
STAT: Signal transducer and activator of transcription
TCCR: Type I T-cell cytokine receptor
TPO: Thrombopoietin
TSLP: Thymic stromal lymphopoietin

 

References