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.
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
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).
EDF: Eosinophil differentiation factor
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
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
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
TSLP: Thymic stromal lymphopoietin
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