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R&D Systems Cytokines, Chemokines and Growth Factors

R&D Systems Cytokines, Chemokines and Growth Factors

Cytokine and Growth Factor Families

 

Cytokines and growth factors are signaling molecules that are involved in most biological processes including embryonic development, cell proliferation and survival, differentiation, and disease pathogenesis. (1). The ability of these molecules to play both beneficial and harmful roles depending on their context is one important hallmark of cytokines and growth factors. For example, although IFN-gamma helps protect the body against intracellular microorganisms, it also plays a role in autoimmune diseases.

Early cytokine research began in the 1940s with studies of “soluble factors” that were produced by one cell and acted on by another cell (1). Stanley Cohen and Rita Levi-Montalcini are credited with discovering the first growth factor, nerve growth factor (NGF), in 1952. Fast forward to 1986, when natural TGF-beta was first purified and sold by R&D Systems, followed by the release of our first recombinant cytokines and growth factors in 1988. Today, we offer a complete range of recombinant proteins that undergo our rigorous quality testing to ensure both high activity and lot-to-lot consistency.

 

Cytokines, Growth Factors, and Small Molecules Testimonial

Read below for more information about the different categories of Cytokines, Chemokines, and Growth factors with links to their cell signaling pathways. You can also view cell signaling pathways categorized by research area.

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Interleukins

Interleukins are secreted cytokines that have complex immunomodulatory functions including cell proliferation, maturation, migration, adhesion, differentiation and activation (2). They are subdivided into several families based on sequence homology, evolutionary relationship, common receptor chain or major function. Known families include the IL-1 family, the common beta and gamma chain families, the IL-6 family, the IL-10 family, the IL-12 family, the IL-17 family, interleukins with chemokine activity, and other interleukins (3).

Interleukin Signaling Pathways

TGF-beta Superfamily – Activin, BMPs, GDFs, GDNF, TGF-beta

Members of the transforming growth factor-beta (TGF-beta) superfamily are important for the development of multicellular organisms. The TGF-beta superfamily signals via heteromeric complexes of type 1 and type 2 serine/threonine kinase receptors. Proteins in this family are involved in cellular processes such as embryonic stem cell self-renewal, gastrulation, differentiation, organ morphogenesis, and adult tissue homeostasis (4). Furthermore, TGF-beta has both pro-tumor and anti-tumor roles.

TGF-Beta Signaling Pathways

Chemokines

Chemotactic cytokines (Chemokines) play important roles in cell migration, immune system development and homeostasis. They are also involved in protective and destructive immune and inflammatory responses (5). Chemokines are organized into four sub-families—CC, CXC, CX3C and XC—which indicate the variation in the configuration of cysteines closest to the N terminus. Chemokines interact with glycosaminoglycans (GAGS), which is important for immobilization on cell surfaces and the extracellular matrix. Chemokines are active as monomers, homodimers and heterodimers. Other post-translational modifications that affect chemokines include citrullination, nitration/nitrosylation, and cleavage by a wide variety of enzymes.

Chemokine Signaling Pathways

FGFs

Fibroblast growth factors (FGFs) were originally identified in the context of promoting fibroblast proliferation. There are 22 FGF family members in humans, of which only 18 are ligands for FGF receptors (FGFRs) (6). Similar to other growth factors, FGFs initiate numerous signaling pathways, including RAS/MAPK, PI3-Kinase/AKT and PLCγ signaling. Many members of the FGF family have been connected to several therapeutic applications including ones for cardiovascular disease, cancer, hair growth, osteoarthritis, diabetes, and Parkinson’s disease among others. The function of several other FGFs remain unidentified.

FGF Signaling Pathways

EGFs

Investigators first became aware of Epidermal growth factor (EGF) during seminal research of the newly discovered nerve growth factor (NGF). EGF was soon shown to be a ligand for the membrane-bound EGF receptor (EGFR), the first described receptor tyrosine kinase (7). EGF and other EGFR ligands (transforming growth factor alpha, amphiregulin, epiregulin, betacellulin, heparain-binding EGF-like growth factor and epigen) all induce EGFR internalization and trafficking to early endosomes. EGFR is upregulated in a variety of cancers, including non-small-cell cancer, metastatic colorectal cancer, glioblastoma, pancreatic cancer, and breast cancer, among others.

Wnts

The Wnt family of secreted growth factors are hydrophobic proteins that mediate contact-dependent or short-distance cell-cell communication (8). Wnt-signaling pathways are divided into canonical, non-canonical and cell-polarity pathways. Using a wide variety of model systems, investigators have shown that Wnt signaling is important for many cellular processes including proliferation, cell-fate specification, differentiation and migration. Although Wnts are commonly associated with development processes, the first mammalian Wnt gene (wnt) was identified as an oncogene. A role for Wnt signaling in cancer is bolstered by in silico data demonstrating frequent alterations (mutations, amplifications, deletions) of Wnt ligands and intracellular components in a variety of cancers (8).

Beta-Catenin-Dependent Wnt Signaling

IGFs

Although Insulin-like growth factors (IGFs), are structurally similar to insulin, they tend to be more important for mediating long-term activities such as cell fate, while insulin is more important for metabolic activity (9). Unlike insulin, which is only secreted by pancreatic β cells, IGF is produced in a variety of tissues, and the specific cell type that secretes it has not been identified. IGF production increases with age into adulthood and declines after the age of 30.

VEGFs

Vascular endothelial growth factors (VEGFs) play important roles in blood vessel formation, maintenance, and remodeling. The VEGF subtypes A-F are high-affinity ligands for the receptor tyrosine kinases, VEGF receptors (VEGFRs) 1, 2, and 3. VEGFs also bind to the co-receptors, neuropilin-1 and neuropilin-2 (NRP1, NRP2) and heparan sulfate proteoglycans (HSPGs) (10). VEGF signaling is regulated by multiple variables including receptor expression, ligand affinity, co-receptor expression, non-VEGF binding-auxiliary proteins and tyrosine phosphatases (10).

VEGF-VEGFR2 Signaling Pathways

CSFs (GM-CSF, M-CSF, G-CSF)

There are four known colony-stimulating factors (CSFs) that are also known as hematopoietic growth factors. These include granulocyte-macrophage-CSF (GM-CSF), macrophage colony formation CSF (M-CSF), granulocyte-CSF (G-CSF) and multi-CSF, also known as interleukin-3 (IL-3). CSFs are glycoproteins that have several functions including stimulating proliferation, suppressing apoptosis, inducing maturation, and promoting differentiation (11).

Angiopoietins

Angiopoietins (Ang-1, Ang-2, Ang-3, and Ang-4) are a family of endothelial cell-specific growth factors that bind to the tyrosine kinase receptor, Tie-2, and are involved in regulating angiogenesis. The Tie-2 growth factor receptor pathway has emerged as a complementary target for vascular endothelial growth factor (VEGF) based anti-angiogenic cancer therapies (12). Although Tie-1 is currently considered an orphan receptor, it is activated via interaction with Tie-2. Increased Ang-2 expression has been correlated with a variety of human cancers including, melanoma, renal cell carcinoma, glioblastoma, breast cancer and colorectal cancer (12). Ang-2 has also been implicated in other ailments such as kidney disease, diabetes, liver cirrhosis asthma and heart disease. Ang-1 expression has also been invoked in some of these ailments, alone and relative to Ang-2 expression.

PDGFs

Platelet-derived growth factor (PDGF) has been shown to promote the proliferation, survival, and migration of cells of mesenchymal origin (13). Various PDGF isoforms play a role in tumorigenesis and neurological diseases. As a therapeutic target, several approaches have been used to inhibit PDGF signaling. These include using antibodies or aptamers to block ligand/receptor binding and PDGF receptor activation as well as using small molecules to block kinase signaling.

TNF Superfamily

Although Tumor Necrosis Factor (TNF) was initially described as a serum factor for inducing tumor necrosis, it is currently a therapeutic target in a variety of immune and inflammatory conditions (14). In addition to having pathogenic roles in inflammation, autoimmunity, tissue degeneration and tumorigenesis, TNF also has homeostatic functions such as regeneration, remyelination and remodeling.

TNF Superfamily Ligand Receptor Interactions

R-Spondin

Members of the roof plate-specific spondin (R-Spondin) growth factor family were initially identified in fetal human brain and the roof plate of the mouse neural tube (15). R-Spondin proteins are known to positively regulate canonical and non-canonical Wingless-related integration site (Wnt) signaling, which is important for organismal development, cellular behavior, and cancer (16). Secreted R-Spondin proteins (RSPO1-4) also function as adult stem cell growth factors and R-Spondin 1 and R-Spondin 3 are now widely used as growth factors for culturing organoids.

IFNs

The term Interferon (IFN) was coined in 1957, to describe a “non-haemagglutinating macro molecular particle” that was shown to be responsible for viral interference (17). Currently, the 22 known IFNs are divided into 3 classes, type I, II and III IFNs. In addition to antiviral effects shared by all IFN classes, class II, which consists of only IFN-gamma, is also a cancer therapeutic target (18).

Type I IFN Signaling Pathways

Type II IFN Signaling Pathways

Type III IFN Signaling Pathways

BDNF

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that also includes nerve growth factor, neurotrophin-3, and neurotrophin-4/5. Several isoforms of BDNF exist, including pre-pro-BDNF, pro-BDNF and mature BDNF (19). The signal sequence of pre-pro-BDNF is cleaved in the golgi apparatus, producing pro-BDNF. Signaling responses to pro-BDNF have been correlated with neuronal fate, development and differentiation. Signaling responses downstream of mature BDNF have been associated with plasticity, neuronal growth, and dendritic branching.

SCF

Stem Cell Factor (SCF) or c-kit ligand (KL) is a widely expressed growth factor that binds to the type III receptor tyrosine kinase, c-kit or Kit to stimulate a number signaling pathways, including MAPK and PI3K/AKT (20). SCF exists in both soluble and transmembrane forms, the regulation of which is determined at the mRNA and protein level. Similar to Flt-3 ligand, SCF stimulates progenitor or stem cell proliferation. Overactivation of c-Kit has been associated with leukemia and the development of gastrointestinal stromal tumors (GISTs) which produce soluble SCF (21)

Flt-3 Ligand

Fms-like target tyrosine kinase 3 ligand (or FLT3L) is a hematopoietic cytokine that functions as a dendritic cell growth factor and is often mutated or overexpressed in leukemia (22). It is structurally similar to SCF and CSF-1 and signals via Fms-like target tyrosine kinase 3 (Flt3), which is class 3 receptor tyrosine kinase receptor. Downstream signaling factors include SHC, Grb2, Gab2, SHIP and the Ras/MAPK, PI3K and STAT pathways.

LIF

Leukemia Inducible Factor (LIF) is an IL-6 family cytokine that was cloned in the late 1980s (23). Recombinant LIF protein is frequently used as a growth factor in stem cell culture media to maintain embryonic stem cell pluripotency. LIF has also been shown to induce macrophage differentiation in mouse M1 myeloid leukemia cells without stimulating progenitor cell proliferation. As such, there was great interest in LIF as a potential therapeutic target for leukemia. Unfortunately, subsequent studies demonstrated that LIF is actually quite pleiotropic (24).

LIF Signaling Pathways

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References

  1. Dinarello, C.A. (2007) Eur. J. Immunol. 37: S34
  2. Brocker, C. et al. (2010) Human Genomics. 5: 30
  3. Akdis, M. et al. (2016) J Allergy Clin Immunol. 138: 984
  4. Weiss, A. and L. Attisano (2013) WIREs Dev Biol. 2: 47
  5. Hughes, C.E. and R.J.B.Nibs (2018) The FEBS Journal. 285:2944
  6. Yun, Y.-R. et al. (2010) Journal of Tissue Engineering. 1:
  7. Wee, P. and Z. Wang. (2017) Cancers. 9: 52
  8. Wiese, K.E. et al. (2018) Development. 145
  9. Hakuno, F. and S. Takahashi (2018) Journal of Molecular Endocrinology. 61: T69
  10. Simons, M. et al. (2016) Molecular Cell Biology 17: 611
  11. Metcalf, D. (2010) Nature Reviews Cancer. 10: 425
  12. Saharinen, P. et al. (2017) Nature Reviews Drug Discovery 16: 635
  13. Papadopoulos, N. and J Lennartsson. (2018) Molecular Aspects of Medicine 62: 75
  14. Kalliolias, G.D. and L.B. Ivashkiv (2016) Nat. Rev. Rheumatol. 12: 49
  15. Jin, Y.R. and J.K.Yoon. (2012) Int. J. Biochem. Cell. 44: 2278
  16. Nusse, R. and H. Varmus. (2012) The EMBO Journal 31: 1
  17. Isaacs, A. and J Lindenmann (1957) Proceedings of the Royal Society B 147: 258
  18. Castro, F. et al. (2018) Frontiers in Immunology 9: 1
  19. Kowianski, P. et al. (2018) Cell. Mol. Neurobiol. 38: 579
  20. Ho, C.C. et al. (2017) Cell. 168: 1041
  21. Lennartsson, J and L. Ronnstrand (2011) Physiol. Rev. 92: 1619
  22. Tsapogas, P. et al. (2017) International Journal of Molecular Sciences. 18:1115
  23. Gearing, D.P. et al. (1987) The EMBO Journal. 6:3995
  24. Mathieu, M-.E. et al. (2012) Stem Cell Reviews. 8:1

 

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