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Introduction

Growth factors are proteins that bind to receptors on the cell surface, with the primary result of activating cellular proliferation and/or differentiation. Many growth factors are quite versatile, stimulating cellular division in numerous different cell types; while others are specific to a particular cell-type. The lists in the following Tables as well as the descriptions of several factors are not intended to be comprehensive nor complete but a look at some of the more commonly known factors and their principal activities.

Factor Principal Source Primary Activity Comments
PDGF platelets, endothelial cells, placenta promotes proliferation of connective tissue, glial and smooth muscle cells two different protein chains form 3 distinct dimer forms; AA, AB and BB
EGF submaxillary gland, Brunners gland promotes proliferation of mesenchymal, glial and epithelial cells  
TGF-a common in transformed cells may be important for normal wound healing related to EGF
FGF wide range of cells; protein is associated with the ECM promotes proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos at least 19 family members, 4 distinct receptors
NGF   promotes neurite outgrowth and neural cell survival several related proteins first identified as proto-oncogenes; trkA (trackA), trkB, trkC
Erythropoietin kidney promotes proliferation and differentiation of erythrocytes  
TGF-b activated TH1 cells (T-helper) and natural killer (NK) cells anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing, inhibits macrophage and lymphocyte proliferation at least 100 different family members
IGF-I primarily liver promotes proliferation of many cell types related to IGF-II and proinsulin, also called Somatomedin C
IGF-II variety of cells promotes proliferation of many cell types primarily of fetal origin related to IGF-I and proinsulin

Cytokines are a unique family of growth factors. Secreted primarily from leukocytes, cytokines stimulate both the humoral and cellular immune responses, as well as the activation of phagocytic cells. Cytokines that are secreted from lymphocytes are termed lymphokines, whereas those secreted by monocytes or macrophages are termed monokines. A large family of cytokines are produced by various cells of the body. Many of the lymphokines are also known as interleukins (ILs), since they are not only secreted by leukocytes but also able to affect the cellular responses of leukocytes. Specifically, interleukins are growth factors targeted to cells of hematopoietic origin. The list of identified interleukins grows continuously with the total number of individual activities now at 22 (13 are listed in the Table below).

Interleukins Principal Source Primary Activity
IL1-a and -b macrophages and other antigen presenting cells (APCs) costimulation of APCs and T cells, inflammation and fever, acute phase response, hematopoiesis
IL-2 activated TH1 cells, NK cells proliferation of B cells and activated T cells, NK functions
IL-3 activated T cells growth of hematopoietic progenitor cells
IL-4 TH2 and mast cells B cell proliferation, eosinophil and mast cell growth and function, IgE and class II MHC expression on B cells, inhibition of monokine production
IL-5 TH2 and mast cells eosinophil growth and function
IL-6 activated TH2 cells, APCs, other somatic cells acute phase response, B cell proliferation, thrombopoiesis, synergistic with IL-1 and TNF on T cells
IL-7 thymic and marrow stromal cells T and B lymphopoiesis
IL-8 macrophages, other somatic cells chemoattractant for neutrophils and T cells
IL-9 T cells hematopoietic and thymopoietic effects
IL-10 activated TH2 cells, CD8+ T and B cells, macrophages inhibits cytokine production, promotes B cell proliferation and antibody production, suppresses cellular immunity, mast cell growth
IL-11 stromal cells synergisitc hematopoietic and thrombopoietic effects
IL-12 B cells, macrophages proliferation of NK cells, INF-g production, promotes cell-mediated immune functions
IL-13 TH2 cells IL-4-like activities
Interferons Principal Source Primary Activity
INF-a and -b macrophages, neutrophils and some somatic cells antiviral effects, induction of class I MHC on all somatic cells, activation of NK cells and macrophages
INF-g activated TH1 and NK cells induces of class I MHC on all somatic cells, induces class II MHC on APCs and somatic cells, activates macrophages, neutrophils, NK cells, promotes cell-mediated immunity, antiviral effects

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Epidermal Growth Factor (EGF)

EGF, like all growth factors, binds to specific high-affinity, low-capacity receptors on the surface of responsive cells. Intrinsic to the EGF receptor is tyrosine kinase activity, which is activated in response to EGF binding. The kinase domain of the EGF receptor phosphorylates the EGF receptor itself (autophosphorylation) as well as other proteins, in signal transduction cascades, that associate with the receptor following activation. Experimental evidence has shown that the Neu proto-oncogene is a homologue of the EGF receptor.
EGF has proliferative effects on cells of both mesodermal and ectodermal origin, particularly keratinocytes and fibroblasts. EGF exhibits negative growth effects on certain carcinomas as well as hair follicle cells. Growth-related responses to EGF include the induction of nuclear proto-oncogene expression, such as Fos, Jun and Myc. EGF also has the effect of decreasing gastric acid secretion.
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Platelet-Derived Growth Factor (PDGF)

PDGF is composed of two distinct polypeptide chains, A and B, that form homodimers (AA or BB) or heterodimers (AB). The c-Sis proto-oncogene has been shown to be homologous to the PDGF A chain. Only the dimeric forms of PDGF interact with the PDGF receptor. Two distinct classes of PDGF receptor have been cloned, one specific for AA homodimers and another that binds BB and AB type dimers. Like the EGF receptor, the PDGF receptors have intrinsic tyrosine kinase activity. Following autophosphorylation of the PDGF receptor, numerous signal-transducing proteins associate with the receptor and are subsequently tyrosine phosphorylated.
Proliferative responses to PDGF action are exerted on many mesenchymal cell types. Other growth-related responses to PDGF include cytoskeletal rearrangement and increased polyphosphoinositol turnover. Again, like EGF, PDGF induces the expression of a number of nuclear localized proto-oncogenes, such as Fos, Myc and Jun. The primary effects of TGF-b are due to the induction, by TGF-b, of PDGF expression.
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Fibroblast Growth Factors (FGFs)

There are at least 19 distinct members of the FGF family of growth factors. The two originally characterized FGFs were identified by biological assay and are termed FGF1 (acidic-FGF, aFGF) and FGF2 (basic-FGF, bFGF). Kaposi's sarcoma cells (prevalent in patients with AIDS) secrete a homologue of FGF called the K-FGF proto-oncogene. In mice the mammary tumor virus integrates at two predominant sites in the mouse genome identified as Int-1 and Int-2. The protein encoded by the Int-2 locus is a homologue of the FGF family of growth factors.
Studies of human disorders as well as gene knock-out studies in mice show the prominent role for FGFs is in the development of the skeletal system and nervous system in mammals. FGFs also are neurotrophic for cells of both the peripheral and central nervous system. Additionally, several members of the FGF family are potent inducers of mesodermal differentiation in early embryos. Non-proliferative effects include regulation of pituitary and ovarian cell function.
The FGFs interact with specific cell-surface receptors. There have been identified 4 distinct receptor types identified as FGFR1 - FGFR4. Each of these receptors has intrinsic tyrosine kinase activity like both the EGF and PDGF receptors. As with all transmembrane receptors that have tyrosine kinase activity, autophosphorylation of the receptor is the immediate response to FGF binding. Following activation of FGF receptors, numerous signal-transducing proteins associate with the receptor and become tyrosine-phosphorylated. The Flg proto-oncogene is a homologue of the FGF receptor family. The FGFR1 receptor also has been shown to be the portal of entry into cells for herpes viruses. FGFs also bind to cell-surface heparan-sulfated proteoglycans with low affinity relative to that of the specific receptors. The purpose in binding of FGFs to theses proteoglycans is not completely understood but may allow the growth factor to remain associated with the extracellular surface of cells that they are intended to stimulate under various conditions.
The FGF receptors are widley expressed in developing bone and several common autosomal dominant disorders of bone growth have been shown to result from mutations in the FGFR genes. The most prevalent is achondroplasia, ACH. ACH is characterized by disproportionate short stature, where the limbs are shorter than the trunk, and macrocephaly (excessive head size). Almost all persons with ACH exhibit a glycine to arginine substitution in the transmembrane domain of FGFR3. This mutation results in ligand-independent activation of the receptor. FGFR3 is predominantly expressed in quiescent chondrocytes where it is responsible for restricting chondrocyte proliferation and differentiation. In mice with inactivating mutations in FGFR3 there is an expansion of long bone growth and zones of proliferating cartilage further demonstrating that FGFR3 is necessary to control the rate and amount of chondrocyte growth.
Several other disorders of bone growth collectively identified as craniosynostosis syndromes have been shown to result from mutations in FGFR1, FGFR2 and FGFR3. Sometimes the same mutation can cause two or more different craniosynostosis syndromes. A cysteine to tyrosine substitution in FGFR2 can cause either Pfeiffer or Crouzon syndrome. This phenomenon indicates that additional factors are likely responsible for the different phenotypes.

Affected Receptor Syndrome Phenotypes
FGFR1 Pfeiffer broad first digits, hypertelorism
FGFR2 Apert mid-face hypoplasia, fusion of digits
FGFR2 Beare-Stevenson mid-face hypoplasia, corrugated skin
FGFR2 Crouzon mid-face hypoplasia, ocular proptosis
FGFR2 Jackson-Weiss mid-face hypoplasia, foot anamolies
FGFR2 Pfeiffer same as for FGFR1 mutations
FGFR3 Crouzon mid-face hypoplasia, acanthosis nigricans, ocular proptosis
FGFR3 Non-syndromatic craniosynostosis digit defects, hearing loss

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Transforming Growth Factors-b (TGFs-b)

TGF-b was originally characterized as a protein (secreted from a tumor cell line) that was capable of inducing a transformed phenotype in non-neoplastic cells in culture. This effect was reversible, as demonstrated by the reversion of the cells to a normal phenotype following removal of the TGF-b. Subsequently, many proteins homologous to TGF-b have been identified. The four closest relatives are TGF-b-1 (the original TGF-b) through TGF-b-5 (TGF-b-1 = TGF-b-4). All four of these proteins share extensive regions of similarity in their amino acids. Many other proteins, possessing distinct biological functions, have stretches of amino-acid homology to the TGF-b family of proteins, particularly the C-terminal region of these proteins.
The TGF-b-related family of proteins includes the activin and inhibin proteins. There are activin A, B and AB proteins, as well as an inhibin A and inhibin B protein. The Mullerian inhibiting substance (MIS) is also a TGF-b-related protein, as are members of the bone morphogenetic protein (BMP) family of bone growth-regulatory factors. Indeed, the TGF-b family may comprise as many as 100 distinct proteins, all with at least one region of amino-acid sequence homology.
There are several classes of cell-surface receptors that bind different TGFs-b with differing affinities. There also are cell-type specific differences in receptor sub-types. Unlike the EGF, PDGF and FGF receptors, the TGF-b family of receptors all have intrinsic serine/threonine kinase activity and, therefore, induce distinct cascades of signal transduction.
TGFs-b have proliferative effects on many mesenchymal and epithelial cell types. Under certain conditions TGFs-b will demonstrate anti-proliferative effects on endothelial cells, macrophages, and T- and B-lymphocytes. Such effects include decreasing the secretion of immunoglobulin and suppressing hematopoiesis, myogenesis, adipogenesis and adrenal steroidogenesis. Several members of the TGF-b family are potent inducers of mesodermal differentiation in early embryos, in particular TGF-b and activin A.
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Transforming Growth Factor-a (TGF-a)

TGF-a, like the b form, was first identified as a substance secreted from certain tumor cells that, in conjunction with TGF-b-1, could reversibly transform certain types of normal cells in culture. TGF-a binds to the EGF receptor, as well as its own distinct receptor, and it is this interaction that is thought to be responsible for the growth factor's effect. The predominant sources of TGF-a are carcinomas, but activated macrophages and keratinocytes (and possibly other epithelial cells) also secrete TGF-a. In normal cell populations, TGF-a is a potent keratinocyte growth factor; forming an autocrine growth loop by virtue of the protein activating the very cells that produce it.
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Erythropoietin (Epo)

Epo is synthesized by the kidney and is the primary regulator of erythropoiesis. Epo stimulates the proliferation and differentiation of immature erythrocytes; it also stimulates the growth of erythoid progenitor cells (e.g. erythrocyte burst-forming and colony-forming units) and induces the differentiation of erythrocyte colony-forming units into proerythroblasts. When patients suffering from anemia due to kidney failure are given Epo, the result is a rapid and significant increase in red blood cell count.
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Insulin-Like Growth Factor-I (IGF-I)

IGF-I (originally called somatomedin C) is a growth factor structurally related to insulin. IGF-I is the primary protein involved in responses of cells to growth hormone (GH): that is, IGF-I is produced in response to GH and then induces subsequent cellular activities, particularly on bone growth. It is the activity of IGF-I in response to GH that gave rise to the term somatomedin. Subsequent studies have demonstrated, however, that IGF-I has autocrine and paracrine activities in addition to the initially observed endocrine activities on bone. The IGF-I receptor, like the insulin receptor, has intrinsic tyrosine kinase activity. Owing to their structural similarities IGF-I can bind to the insulin receptor but does so at a much lower affinity than does insulin itself.
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Insulin-Like Growth Factor-II (IGF-II)

IGF-II is almost exclusively expressed in embryonic and neonatal tissues. Following birth, the level of detectable IGF-II protein falls significantly. For this reason IGF-II is thought to be a fetal growth factor. The IGF-II receptor is identical to the mannose-6-phosphate receptor that is responsible for the integration of lysosomal enzymes (which contain mannose-6-phosphate residues) to the lysosomes.
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Interleukin-1 (IL-1)

IL-1 is one of the most important immune response-- modifying interleukins. The predominant function of IL-1 is to enhance the activation of T-cells in response to antigen. The activation of T-cells, by IL-1, leads to increased T-cell production of IL-2 and of the IL-2 receptor, which in turn augments the activation of the T-cells in an autocrine loop. IL-1 also induces expression of interferon-g (IFN-g) by T-cells. This effect of T-cell activation by IL-1 is mimicked by TNF-a which is another cytokine secreted by activated macrophages. There are 2 distinct IL-1 proteins, termed IL-1-a and -1-b, that are 26% homologous at the amino acid level. The IL-1s are secreted primarily by macrophages but also from neutrophils, endothelial cells, smooth muscle cells, glial cells, astrocytes, B- and T-cells, fibroblasts and keratinocytes. Production of IL-1 by these different cell types occurs only in response to cellular stimulation. In addition to its effects on T-cells, IL-1 can induce proliferation in non-lymphoid cells.
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Interleukin-2 (IL-2)

IL-2, produced and secreted by activated T-cells, is the major interleukin responsible for clonal T-cell proliferation. IL-2 also exerts effects on B-cells, macrophages, and natural killer (NK) cells. The production of IL-2 occurs primarily by CD4+ T-helper cells. As indicated above, the expression of both IL-2 and the IL-2 receptor by T-cells is induced by IL-1. Indeed, the IL-2 receptor is not expressed on the surface of resting T-cells and is present only transiently on the surface of T-cells, disappearing within 6-10 days of antigen presentation. In contrast to T-helper cells, NK cells constitutively express IL-2 receptors and will secrete TNF-a, IFN-g and GM-CSF in response to IL-2, which in turn activate macrophages.
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Interleukin-6 (IL-6)

IL-6 is produced by macrophages, fibroblasts, endothelial cells and activated T-helper cells. IL-6 acts in synergy with IL-1 and TNF-( in many immune responses, including T-cell activation. In particular, IL-6 is the primary inducer of the acute-phase response in liver. IL-6 also enhances the differentiation of B-cells and their consequent production of immunoglobulin. Glucocorticoid synthesis is also enhanced by IL-6. Unlike IL-1, IL-2 and TNF-a, IL-6 does not induce cytokine expression; its main effects, therefore, are to augment the responses of immune cells to other cytokines.
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Interleukin-8 (IL-8)

IL-8 is an interleukin that belongs to an ever-expanding family of proteins that exert chemoattractant activity to leukocytes and fibroblasts. This family of proteins is termed the chemokines. IL-8 is produced by monocytes, neutrophils, and NK cells and is chemoattractant for neutrophils, basophils and T-cells. In addition, IL-8 activates neutrophils to degranulate.
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Tumor Necrosis Factor-a (TNF-a)

TNF-a (also called cachectin), like IL-1 is a major immune response-- modifying cytokine produced primarily by activated macrophages. Like IL-1, TNF-a induces the expression of other autocrine growth factors, increases cellular responsiveness to growth factors and induces signaling pathways that lead to proliferation. TNF-a acts synergistically with EGF and PDGF on some cell types. Like other growth factors, TNF-a induces expression of a number of nuclear proto-oncogenes as well as of several interleukins.
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Tumor Necrosis Factor-b (TNF-b)

TNF-b (also called lymphotoxin) is characterized by its ability to kill a number of different cell types, as well as the ability to induce terminal differentiation in others. One significant non-proliferative response to TNF-b is an inhibition of lipoprotein lipase present on the surface of vascular endothelial cells. The predominant site of TNF-b synthesis is T-lymphocytes, in particular the special class of T-cells called cytotoxic T-lymphocytes (CTL cells). The induction of TNF-b expression results from elevations in IL-2 as well as the interaction of antigen with T-cell receptors.
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Interferon-g (INF-g)

IFN-a, IFN-b and IFN-w are known as type I interferons: they are predominantly responsible for the antiviral activities of the interferons. In contrast, IFN-g is a type II or immune interferon. Although IFN-g, has antiviral activity it is significantly less active at this function than the type I IFNs. Unlike the type I IFNs, IFN-g is not induced by infection nor by double-stranded RNAs. IFN-g is secreted primarily by CD8+ T-cells. Nearly all cells express receptors for IFN-g and respond to IFN-g binding by increasing the surface expression of class I MHC proteins, thereby promoting the presentation of antigen to T-helper (CD4+) cells. IFN-g also increases the presentation of class II MHC proteins on class II cells further enhancing the ability of cells to present antigen to T-cells.
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Colony Stimulating Factors (CSFs)

CSFs are cytokines that stimulate the proliferation of specific pluripotent stem cells of the bone marrow in adults. Granulocyte-CSF (G-CSF) is specific for proliferative effects on cells of the granulocyte lineage. Macrophage-CSF (M-CSF) is specific for cells of the macrophage lineage. Granulocyte-macrophage-CSF (GM-CSF) has proliferative effects on both classes of lymphoid cells. Epo is also considered a CSF as well as a growth factor, since it stimulates the proliferation of erythrocyte colony-forming units. IL-3 (secreted primarily from T-cells) is also known as multi-CSF, since it stimulates stem cells to produce all forms of hematopoietic cells.
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Michael W. King, Ph.D / Medical Biochemistry / Terre Haute Center for Medical Education / memwk@thcme.indstate.edu
Last modified:   Friday, 29-Dec-00 20:33:20