Growth Factors and Cytokines: Classification and Nomenclature

By: Jennifer Fries, BioFiles 2009, 4.5, 4.

Growth factors and cytokines have historically been classified into ‘families’ based on their apparent activity and/or impact on a given cell type, system, or tissue. Lately however, there has been an effort to establish naming based upon growth factor and cytokine receptors. Growth factor and cytokine receptors are highly conserved, and by utilizing them as a key for developing a systematic naming process, the field of growth factor families has narrowed.

Naming based on the differentiation of the cytosolic receptor domains has resulted in several major ‘families’ of growth factors and cytokines. In addition, the extracellular domains of these receptors demonstrate considerable homologies. This degree of homology in the extracellular domain leads to the highly conserved structures of growth factors and cytokines. The conserved nature of these receptors accounts for multiple signal transduction pathways effecting or impacting similar processes.

The identification, origin, activity, and signal transduction pathways of growth factors and cytokines remains in the discovery phase, however some of the more established, influential, and common compounds have been characterized. In recent years, cell biologists have attempted to reach a consensus on naming and nomenclatures, however naming schemes previously have been rather chaotic, leaving some compounds in rather odd groups. For example, bone morphogenic proteins (BMP), which affect bone and cartilage formation, fall into the tumor growth factor-beta (TGF-b) super-family. Another example is the tumor necrosis factor (TNF) protein. It is not useful as an anti-tumor therapy, but is highly active in immune modulation and inflammation.

Cytokines are often referred to as “growth factors”, but the reverse is not necessarily the case. Historically, growth factors have been thought of as compounds that have a positive effect on cell growth and expansion while cytokines are typically considered to have an immunological or hematopoietic response. Cytokines such as interleukin-2 (IL-2), which promote long term growth of activated T cells and related cell types fit the ‘growth factor’ description, but are classified as cytokines for their immunological responses and molecules such as the FAS ligands, which are involved in the initiation of programmed cell death—certainly not a positive effect on cell growth and expansion—fall into the cytokine category.

Over the years these compounds have been categorized into various classes, families, and super families, including the bone morphogenic proteins, epidermal growth factors, fibroblast growth factors, interferons, transforming growth factors, tumor necrosis factors, and vascular endothelial growth factors. As new molecules and pathways are identified, the terms ‘growth factor’ and ‘cytokine’ have come to be used interchangeably.

The following table provides an overview of key cytokine and growth factor groups by receptor family as well as by classical family names and demonstrates the present characteristics and functionality at the family level.

Receptor Family Receptor Characteristics Members Common Activity Cytokine Characteristics
Hematopoietin – type 1 Cytosolic box 1 / 2 IL-6R G-CSFR gp130 IL-12R T/B cell activation 4 α-helical bundles
  WSXWS extracellular sequence LIFR IL-2Rβ IL-2Rγ IL-4R IL-3Rα IL-9R GM-CSFR IL-5R Hematoiesis 4 α-helical bundles
Interferon – type 2 Cytosolic box 1 / 2, Extracellular Fibronectin domain IFN-α/βR IFN-R-α/β IL-10R Anti-viral (not IL-10) 4 α-helical bundles
Tumor Necrosis Factor Cytosolic death domain Four Cys-rich extracellular regions P55 TNFR P75 TNRR (no death domain) LTβR NGFR CD40 CD30 CD27 4-1BB OX40 TRAMP (DR3) TRAILR (DR4) Proinflammatory Jelly roll motif
Interleukin-1 / Toll-like Cytosolic Toll / IL- 1R (TIR) domain Ig domains (IL-1R) Leucine-rich repeats (extracellular TLR subgroup) IL-1RI IL-1RII(no TIR) IL-1RacP IL018R α/β- chains T1/ST2 IL-1RAPL SIGIRR TLR1- TLR10 Proinflammatory β-trefoil
Tyrosine Kinase Cytosolic tyrosine kinase domain M-CSFR EGFR TGF IGFs FGF’s Growth Factors β-sheet
Chemokine 7 trans-membrane regions IL-8 MCP’s RANTES Eotaxin Chemotaxis Triple-stranded antiparallel β-sheet Greek key motif
(from The Cytokine Facts Book, 2nd Ed. Fitzgerald et al, Academic Press, 2001)

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