Home Protein ExpressionCytokine Receptors (Hematopoetin Receptor Family)

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 Rγ_c (a common chain in IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptor complexes), Rβ_c (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 Rγ_c and Rβ_c), 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 For^a	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 Agonists^a,b	IL-2 (I2644, I7908 (h), I0523 (m)) IL-4 (I4269 (h), I1020 (m), I3650 (r)) IL-7 (I5896 (h), I4892 (m)) IL-15 (I8648)	IL-3 (I1646, I7389 (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 For^a	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 Agonists^a,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 (I2644, I7908) 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 For^a	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 Agonists^a,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 Agonists^a,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 Agonists^a,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.sigmaaldrich.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

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