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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.

 

 

 

 

 

 

 

 

 

 

 

Cytokines are a class of signaling proteins that are used extensively in cellular communication, immune function and embryogenesis. Cytokines are produced by a variety of hematopoietic and non-hematopoietic cell types and can exert autocrine, paracrine and endocrine effects as do the hormones. They are, therefore, more correctly related to hormones than to growth factors in their overall functions. However, many cytokines also exhibit growth factor activity so they are discussed here as well as in the Peptide Hormones page.

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.

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Growth Factors

Factor Principal Source Primary Activity Comments
PDGF platelets, endothelial cells, placenta promotes proliferation of connective tissue, glial and smooth muscle cells represents a family of four peptides encoded by four distinct genes: A, B, C, and D; these four peptides form either homo- or heterodimers such that five distinct biologically active PDGF isoforms (AA, AB, BB, CC, DD) result
EGF submaxillary gland, Brunners gland promotes proliferation of mesenchymal, glial and epithelial cells represents the founding member of the EGF-family of proteins that includes, but is not limited to, transforming growth factor-α (TGF-α), amphiregulin, and the neuregulins (neuregulin-1, -2, -3, and -4)
TGF-α macrophages, keratinocytes, hypothalamic astrocytes; commonly expressed by transformed cells important for normal wound healing, cellular proliferation, female reproductive maturation, embryogenesis is a member of the EGF-family of proteins; functions by binding to the EGF receptor
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 18 family members, 5 distinct receptors
NGF mast cells, eosinophils, bone marrow stromal cells, keratinocytes promotes neurite outgrowth and neural cell survival member of a family of proteins termed neurotrophins that promote proliferation and survival of neurons; neurotrophin receptors are a class of related proteins first identified as proto-oncogenes: TrkA ("trackA"), TrkB, TrkC
Erythropoietin kidney promotes proliferation and differentiation of erythrocytes  
TGF-β 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-1 primarily liver promotes proliferation of many cell types related to IGF-2 and proinsulin, also called somatomedin C
IGF-2 variety of cells promotes proliferation of many cell types primarily of fetal origin related to IGF-1 and proinsulin

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Interleukins and Cytokines

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 (18 are listed in the Table below).

Interleukins Principal Source Primary Activity
IL1-α and -β macrophages and other antigen presenting cells (APCs) co-stimulation 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 such as hepatocytes and adipocytes acute phase response, B cell proliferation, thrombopoiesis, synergistic with IL-1β 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 bone marrow stromal cells synergisitc hematopoietic and thrombopoietic effects
IL-12 B cells, T cells, macrophages, dendritic cells proliferation of NK cells, INF-γ production, promotes cell-mediated immune functions
IL-13 Th2 cells, B cells, macrophages stimulates growth and proliferation of B cells, inhibits production of macrophage inflammatory cytokines
IL-14 T cells and malignant B cells regulates the growth and proliferation of B cells
IL-15 virus infected macrophages, mononuclear phagocytes induces production of NK cells
IL-16 eosinophils, CD8+ T cells, lymphocytes, epithelial cells chemoattractant for CD4+ cells
IL-17: six isoforms all from different genes;
IL-17A, B, C, D, E, and F (IL-17E also called IL-25)
A and F forms only expressed in a subset of T cells; B expressed in leukocytes and peripheral tissues; C up-regulated during inflammation; D expressed in nervous system and skeletal muscle; E expressed in peripheral tissues increases production of inflammatory cytokines, angiogenesis, affects endothelial and epithelial cells
IL-18 macrophages increases NK cell activity, induces production of INF-γ
Interferons Principal Source Primary Activity
INF-α and -β macrophages, neutrophils and some somatic cells antiviral effects, induction of class I MHC on all somatic cells, activation of NK cells and macrophages
INF-γ 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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Adipocytokines

Adipose tissue is not merely an organ designed to passively store excess carbon in the form of fatty acids esterified to glycerol (triacylglycerols). Mature adipocytes synthesize and secrete numerous enzymes, growth factors, cytokines and hormones that are involved in overall energy homeostasis. Many of the factors that influence adipogenesis are also involved in diverse processes in the body including lipid homeostasis and modulation of inflammatory responses. In addition, a number of proteins secreted by adipocytes play important roles in these same processes. In fact recent evidence has demonstrated that many factors secreted from adipocytes are proinflammatory mediators and these proteins have been termed adipocytokines or adipokines. Members of this class of protein secreted from adipocytes include TNF-α, IL-6 and leptin. Listed in the Table below is only a subset of proteins known to be secreted by adipose tissue and the focus is on those that effect overall metabolic homeostasis and modulate inflammatory processes. As is clear from the Table, not all the proteins are unique to adipose tissue.


Factor Principal Source Major Action
adiponectin
also called adipocyte complement factor 1q-related protein (ACRP30), and adipoQ
adipocytes see Adipose Tissue page
adipsin (also called complement factor D) adipocytes, liver, monocytes, macrophages rate limiting enzyme in complement activation
apelin adipocytes, vascular stromal cells, heart levels increase with increased insulin, exerts positive hemodynamic effects, may regulate insulin resistance by facilitating expression of BAT uncoupling proteins (e.g. UCP1, thermogenein)
chemerin adipocytes, liver modulates expression of adipocyte genes involved in glucose and lipid homeostasis such as GLUT4 and fatty acid synthase (FAS); potent anti-inflammatory effects on macrophages expressing the chemerin receptor (chemokine-like receptor-1, CMKLR1)
C-reactive protein (CRP) hepatocytes, adipocytes is a member of the pentraxin family of calcium-dependent ligand binding proteins; assists complement interaction with foreign and damaged cells; enhances phagocytosis by macrophages; levels of expression regulated by circulating IL-6; modulates endothelial cell functions by inducing expression of various cell adhesion molecules, e.g. ICAM-1, VCAM-1, and selectins; induces MCP-1 expression in endothelium; attenuates NO production by downregulating NOS expression; increase expression and activity of PAI-1
IL-6 adipocytes, hepatocytes, activated Th2 cells, and antigen-presenting cells (APCs) acute phase response, B cell proliferation, thrombopoiesis, synergistic with IL-1 and TNF on T cells
leptin predominantly adipocytes, mammary gland, intestine, muscle, placenta see Adipose Tissue page
monocyte chemotactic protein-1 (MCP-1) leukocytes, adipocytes is a chemokine defined as CCL2 (C-C motif, ligand 2); recruits monocytes, T cells, and dendritic cells to sites of infection and tissue injury
omentin visceral stromal vascular cells of omental adipose tissue the omentum is one of the peritoneal folds that connects the stomach to other abdominal tissues, enhances insulin-stimulated glucose transport, levels in the blood inversely correlated with obesity and insulin resistance
plasminogen-activator inhibitor-1 (PAI-1) adipocytes, monocytes, placenta, platelets, endometrium see the Blood Coagulation page for more details
resistin adipocytes, spleen, monocytes, macrophages, lung, kidney, bone marrow, placenta see Adipose Tissue page
TNFα primarily activated macrophages, adipocytes induces expression of other autocrine growth factors, increases cellular responsiveness to growth factors and induces signaling pathways that lead to proliferation
vaspin visceral and subcutaneous adipose tissue is a serine protease inhibitor, levels decrease with worsening diabetes, increase with obesity and impaired insulin sensitivity
visfatin; also called pre-B cell colony-enhancing factor (PBEF); these two independent activities are identical to the enzyme nicotinamide phosphoribosyltransferase (NAMPT) ubiquitously expressed with highest levels of expression in visceral white adipose tissue was originally reported to have insulin mimetic effects but that paper was subsequently retracted; the intracellular version of NAMPT (sometimes referred to as iNAMPT) has nicotinamide phosphoribosyltransferase activity; the extracellular version (eNAMPT) exhibits cytokine-like activity; conflicting results relative to insulin receptor binding but blocking insulin receptor signaling interferes with effects of eNAMPT; changes in NAMPT activity occur during fasting and positively regulate the activity of the NAD+-dependent deacetylase, SIRT1, leading to alterations in gene expression

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Epidermal Growth Factor (EGF)

EGF is synthesized as a preproprotein that is processed to a 53 amino acid functional growth factor. The EGF preproprotein is derived from the EGF gene which is located on chromosome 4q25 and is composed of 26 exons that generate three alternatively spliced mRNAs. Like all growth factors, EGF binds to specific high-affinity, low-capacity receptors (EGFR) 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. The primary signal transduction cascade initiated in response to EGF binding its receptor is MAP kinase pathway.

The EGF receptor is derived from the EGFR gene which is located on chromosome 7p12 and is composed of 30 exons that generate four alternatively spliced mRNAs, each of which encode a distinct protein. The major transmembrane-spanning EGF receptor is derived from the EGFR isoform a encoding mRNA. This precursor protein is composed of 1210 amino acids. The EGFR isoforms b, c, and d mRNAs encoded proteins that only contain the extracellular domain of the full-length isoform a receptor. 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 exerts effects on metabolic processes such as decreasing gastric acid secretion, and increasing the rate of glycolysis.

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Platelet-Derived Growth Factor (PDGF)

The PDGF is either a homodimeric or heterodimeric growth factor. The PDGF composition is determined by the expression of four distinct polypeotides encoded by four different genes. The PDGF peptides are identified as PDGF-A, -B, -C, and -D. These four PDGF peptides result in five distinct dimeric forms of PDGF (PDGF-AA, -AB, -BB, -CC, and -DD). The SIS proto-oncogene has been shown to be homologous to the PDGF-B peptide. Only dimeric forms of PDGF interact with the PDGF receptors. The PDGF-A preproprotein is derived from the PDGFA gene which is located on chromosome 7p22 and is composed of 9 exons that generate two alternatively spliced mRNAs. PDGF-A isoform 1 is a 211 amino acid preproprotein and isoform 2, which lacks the coding information from exon 6, is a 196 amino acid preproprotein. The PDGF-B preproprotein is derived from the PDGFB gene which is located on chromosome 22q13.1 and is composed of 8 exons that generate two alternatively spliced mRNAs. PDGF-B isoform 1 is a 241 amino acid preproprotein. The PDGF-B isoform 2 protein may not undergo processing to a function protein. The PDGF-C preproprotein is derived from the PDGFC gene which is located on chromosome 4q32 and is composed of 9 exons that encode a 345 amino acid preproprotein. The PDGF-D preproprotein is derived from the PDGFD gene which is located on chromosome 11q22.3 and is composed of 7 exons that generate two alternatively spliced mRNAs. PDGF-D isoform 1 is a 370 amino acid preproprotein ans PDGF-D isoform 2 is a 364 amino acid preproprotein.

Three distinct forms of the PDGF receptor have been identified that result from the dimerization of proteins expressed from two different genes. The composition of these three receptor types are αα, αβ, and ββ. 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. The PDGF receptor α (alpha) protein is encoded by the PDGFRA gene which is located on chromosome 4q12 and is composed of 28 exons that encode a 1089 amino acid precursor protein. The PDGF receptor β (beta) protein is encoded by the PDGFRB gene which is located on chromosome 5q33.1 and is composed of 26 exons that encode a amino acid precursor protein. The PDGF-AA isoform binds exclusively to the PDGFR-αα type receptor. The PDGF-BB isoform can bind to all three types for PDGFR. The PDGF-AB isoform binds to the PDGFR-αα and PDGFR-αβ type receptors. The PDGF-CC isoform, like the PDGF-AB isoforms, specifically binds to the PDGFR-αα and PDGFR-αβ type receptors. The PDGF-DD isoform binds with highest affinity to the PDGFR-ββ type receptors.

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. Indeed, the primary effects of TGF-β are due to the induction, by TGF-β, of PDGF expression.

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Fibroblast Growth Factors (FGFs)

There are currently 18 members of the mammalian FGF family of growth factors. These members are numbered FGF1–FGF10 and FGF16–FGF23. These 18 proteins are divided into six different FGF families based upon differences in sequence homology. Family 1 (FGF 1 subfamily) is composed of FGF1 and FGF2; family 2 (FGF7 subfamily) is composed of FGF3, FGF7, FGF10, and FGF22; family 3 (FGF4 subfamily) is composed of FGF4, FGF5, and FGF6; family 4 (FGF8 subfamily) is composed of FGF8, FGF17, and FGF18; family 5 (FGF9 subfamily) is composed of FGF9, FGF16, and FGF20; family 6 (FGF19 subfamily) is composed of FGF19, FGF21, and FGF23. In addition, there are four FGFs that do not belong to these six families (FGF11–FGF14; also referred to as the FGF11 subfamily) and although they do have sequence homology to members of the six families they do not activate the FGF receptors and are thus, not considered members of the FGF family but are FGF homologous factors. Of note is the fact that human FGF19 is the orthologue of mouse FGF15.

The two originally characterized FGFs were identified by biological assay and are termed FGF1 (acidic-FGF, aFGF) and FGF2 (basic-FGF, bFGF). 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 turned out to be a homologue of the FGF family of growth factors and is now called FGF3. Kaposi's sarcoma cells (prevalent in patients with AIDS) were found to secrete a homologue of FGF originally called the K-FGF proto-oncogene, it is now known as FGF4.

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 members of the first five families of FGFs all function in a paracrine manner (meaning the target tissue is near the site of hormone synthesis and release).

The sixth FGF family (members FGF19, FGF21, and FGF23) each act in an endocrine manner (meaning the target tissue is distant from the site of hormone synthesis and release) to regulate glucose, cholesterol, bile acid, vitamin D, and phosphate homeostasis. Although FGF19, FGF21, and FGF23 interact with known FGF receptors they do so only in the presence of a binding partner. This binding partner is identified as Klotho (also known as αKlotho). The Klotho gene was originally isolated from a mouse model of age-related disorders and thus the gene was named after the Fate of Greek mythology who spins the thread of life. Subsequent to the isolation of the αKlotho gene another related gene termed βKlotho was identified. Both αKlotho and βKlotho are involved in the interactions of FGF19, FGF21, and FGF23 with FGF receptors. Although these three FGFs belong to a distinct FGF subfamily and each acts as an endocrine factor they have distinct physiological roles. FGF19 is involved in the control of cholesterol and bile acid synthesis. FGF21 in involved in the regulation of glucose and lipid homeostasis. FGF23 is a potent regulator of vitamin D and phosphate metabolism.

The FGFs interact with specific cell-surface receptors. There have been identified five distinct receptor types identified as FGFR1–FGFR5. 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 widely 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. For additional information on the craniosynostosis syndromes see the GeneReviews page on these disorders.


Affected Receptor Syndrome Phenotypes
FGFR1 Pfeiffer craniosynostosis (premature skull bone fusion); hypertelorism (wide-spaced eyes); micrognathia (small jaw); beaked nose; high forehead; brachydactyly (short fingers and toes); syndachtyly (digit fusion); autosomal dominant inheritance; type 1 disease associated with either FGFR1 or FGFR2 mutaitons, type 2 and 3 disease caused by FGFR2 mutations only
FGFR2 Apert craniosynostosis (premature skull bone fusion); fusion of digits; mild to moderate mental retardation; autosomal dominant inheritance
FGFR2 Beare-Stevenson craniosynostosis (premature skull bone fusion); cutis gyrata (corrugated skin); acanthosis nigricans (thick, dark skin patches); fewer than 20 person world-wide known to have disease; autosoaml dominant inheritance
FGFR2 Crouzon craniosynostosis (premature skull bone fusion); ocular proptosis (eyeball protrusion); hearing loss; underdeveloped upper jaw; autosomal dominant inheritance
FGFR2 Jackson-Weiss craniosynostosis (premature skull bone fusion); syndachtyly; wide and short big toes that point away from other toes; autosomal dominant inheritance
FGFR2 Pfeiffer same as for FGFR1 mutations
FGFR3 Achondroplasia short-limbed dwarfism; macrocephaly; lordosis (sway back); bowed legs; kyphosis (abnormal front-to-back spine curvature); autosomal dominant inheritance; 80% due to new mutaitons, highly correlated to increased age of father
FGFR3 Crouzonodermoskeletal syndrome craniosynostosis (premature skull bone fusion); acanthosis nigricans; beaked nose; underdeveloped upper jaw; ocular proptosis; strabismus (eyes that point in different directions); autosomal dominant inheritance

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Transforming Growth Factors-β (TGFs-β)

A more detailed description of the TGF-β family of growth factors and associated signaling pathways can be found on the Signaling by Wnts and TGFs-β/BMP page.

TGF-β 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-β. Subsequently, many proteins homologous to TGF-β have been identified. The four closest relatives are TGF-β1 (the original TGF-β) through TGF-β5 (TGF-β1 is the same as TGF-β4). 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-β family of proteins, particularly the C-terminal region of these proteins.

The TGF-β-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-β-related protein, as are members of the bone morphogenetic protein (BMP) family of bone growth-regulatory factors. Indeed, the TGF-β 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-β with differing affinities. There also are cell-type specific differences in receptor sub-types. Unlike the EGF, PDGF and FGF receptors, the TGF-β family of receptors all have intrinsic serine/threonine kinase activity and, therefore, induce distinct cascades of signal transduction.

TGFs-β have proliferative effects on many mesenchymal and epithelial cell types. Under certain conditions TGFs-β 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-β family are potent inducers of mesodermal differentiation in early embryos, in particular TGF-β and activin A.

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Transforming Growth Factor-α (TGF-α)

TGF-α, like the original founding member of the TGF-β family, was first identified as a substance secreted from certain tumor cells that, in conjunction with TGF-β1, could reversibly transform certain types of normal cells in culture. The TGF-α precursor protein is derived from the TGFA gene which is located on chromosome 2p13 and is composed of 7 exons that generate four alternatively spliced mRNAs. The predominant TGF-α preproprotein contains 160 amino acids. Following processing of the preproprotein, TGF-α can be function as a transmembrane-bound ligand or it can be fully processed to the secreted extracellular growth factor form. TGF-α binds to the EGF receptor and it is this interaction that is responsible for the growth factor's effect. The predominant sources of TGF-α are carcinomas, but activated macrophages, keratinocytes (and possibly other epithelial cells), and hypothalamic astrocytes also produce and secrete TGF-α. In normal cell populations, TGF-α is a potent keratinocyte growth factor; forming an autocrine growth loop by virtue of the protein activating the very cells that produce it. Within the brain, TGF-α regulates the synthesis and release of the anterior pituitary hormone, luteinizing hormone-releasing hormone, LHRH. This latter effect of TGF-α is important in the maturation of the secondary female sex characteristics.

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Erythropoietin (EPO)

EPO is synthesized principally by the kidney and is the primary regulator of erythropoiesis. Although EPO is synthesized by the fetal liver, this source is of no significance to the adult. 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. The EPO precursor protein is derived from the EPO gene which is located on chromosome 7q22 and is composed of 5 exons. The EPO proecursor is composed of 193 amino acids. The effects of EPO are exerted in response to the hormone binding to a specific EPO receptor. Activation of the EPO receptor results in signal transduction events involving the Jak/STAT pathway. The EPO receptor is derivced from the EPOR gene which is located on chromosome 19p13.2 and is composed of 8 exons that encode a 508 amino acid precursor protein. When patients suffering from anemia, due to kidney failure or as a result of cancer therapy, are given human recombinant EPO, the result is a rapid and significant increase in red blood cell count.

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Insulin-Like Growth Factor-1 (IGF-1)

IGF-1 (originally called somatomedin C) is a growth factor structurally related to insulin. IGF-1 is the primary protein involved in responses of cells to growth hormone (GH): that is, IGF-1 is produced in response to GH and then induces subsequent cellular activities. It is the activity of IGF-1, in response to GH, that gave rise to the term somatomedin. Subsequent studies demonstrated that IGF-1 has autocrine and paracrine activities in addition to the initially observed endocrine activities on bone. IGF-1 belongs to the insulin-like growth factor system that includes IGF-1, IGF-2 (described in the next section), IGF binding proteins, and the receptors that bind the growth factors.

The IGF-1 precursor is derived from the IGF1 gene which is located on chromosome 12q23.2 and is composed of 7 exons that generate multiple mRNAs via alternative splicing and alternative polyadenylation site utilization. In addition, IGF1 gene expression is controlled by multiple transcriptional initiation sites. Two classes of IGF-1 mRNA result from this complex control such that class 1 mRNAs initiate from promoter elements in exon 1, whereas class 2 mRNAs initiate from promoters in exon 2. IGF-1 mRNAs initiating from promoter 1 in exon 1 are found in multiple tissues, whereas, transcriptional initiation from promoter 2 in exon 2 is restricted to the liver and the kidney. Expression of the IGF-1 gene in the liver is the major source of secreted IGF-1 hormone accounting for 75% of total serum IGF-1. The longest IGF-1 preproprotein contains 158 amino acids. Despite the complex transcriptional regulation and the generation of multiple prepro-IGF-1 proteins, all of the resultant mature hormones are 70 amino acids in length.

IGF-1 exerts its biological effects primarily as a resutl of binding to, and activating, the IGF-1 receptor. The IGF-1 receptor (IGF1R), like the insulin receptor, is composed of disulfide bonded α- and β-peptides that are derived by proteolytic processing of the primary translation product. In addition, like the insulin receptor, the IGF1R has intrinsic tyrosine kinase activity. Owing to their structural similarities IGF-1 can bind to the insulin receptor but does so at a much lower affinity than does insulin itself. The IGF1R gene is located on chromsome 15q26.3 and is composed of 24 exons that generate two alternatively spliced mRNAs encoding IGF1R isoform 1 precursor (1367 amino acids) and isoform 2 precursor (1366 amino acids).

In addition to binding to the IGF-1 receptor, IGF-1 activity (as well as IGF-2 activity, see next section) is controlled by binding to one of several IGF binding proteins (IGFBP). Humans express six IGFBPs (IGFBP1–IGFBP6) that sequester IGFs in serum resulting in control of their interaction with IGF receptors. About 75% of circulating IGFs are bound in ternary complexes that are composed of IGF-1 or IGF-2, IGFBP-3 and IGFBP acid-labile subunit (IGFALS). IGFALS is synthesized by, and secreted from, the liver. The IGFBP1 gene is located on chromosome 7p12.3 and is composed of 4 exons that encode a 259 amino acid precursor protein. The IGFBP2 gene is located on chromosome 2q35 and is composed of 4 exons that generate four alternatively spliced mRNAs encoding three distinct precursor proteins, only one of which is secreted. The IGFBP3 gene is located on chromosome 7p12.3 and is composed of 5 exons that generate two altetrnatively spliced mRNAs encoding isoform a precursor (297 amino acids) and isoform b precursor (291 amino acids). The IGFBP4 gene is located on chromosome 17q21.2 and is composed of 4 exons that encode a 258 amino acid precursor protein. The IGFBP5 gene is located on chromosome 2q35 and is composed of 4 exons that encode a 272 amino acid precursor protein. The IGFBP6 gene is located on chromosome 12q13 and is composed of 4 exons that encode a 240 amino acid precursor protein. The IGFALS gene is located on chromosome 16p13.3 and is composed of 4 exons that generate two alternatively spliced mRNAs encoding two distinct precusor proteins.

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Insulin-Like Growth Factor-2 (IGF-2)

Like IGF-1, IGF-2 is a growth factor that is structurally related to insulin and shares 67% amino acid identity with IGF-1. IGF-2 is almost exclusively expressed in embryonic (fetal and placental) and neonatal tissues. Following birth, in humans, the level of IGF-2 rises in early childhood and remains relatively steady throughout adulthood until old age when it declines. During adult life the level of serum IGF-2 is approximately 3 times that of IGF-1. Due to the fetal and placental expression of IGF-2, it was originally thought to be primarily a fetal growth factor. However, evidence clearly indicates that IGF-2 does indeed exert important metabolic effects in the adult. The primary tissue responsible for adult IGF-2 expression is the liver. The IGF2 gene is located on chromosome 11p15.5 and is composed of 9 exons that generate five alternatively spliced mRNAs that collectively encode two distinct preproproteins of 236 and 180 amino acids. The 236 amino acid preproprotein originates from translational initiation at an upstream AUG codon not found in two of the other four mRNA splice variants. Prepro-IGF-2 contains a 24-amino acid signal peptide. Within the Golgi apparatus, pro-IGF-2 is O-glycosylated and then further proteolyzed to the mature IGF-2 form via the action of prohormone convertase 4. Post-translational processing of IGF-2 is an incomplete process such that several pro-IGF-2 peptides (collectively referred to as "big" IGF-2) are secreted into the blood, accounting for 10%–20% of total serum IGF-2.

Expression of the IGF2 gene is controlled by the epigenetic phenomenon of genomic imprinting. Expression of the IGF2 gene is restricted to the paternal allele, in most tissues, via the imprinting phenomenon. The IGF-2 gene also contains four promoters (identified as P1–P4) from which IGF-2 is transcribed. The P2–P4 promoters control IGF-2 transcription in the embryo, whereas transcription occurs from all four promoters in the liver of adult humans. Expression of the IGF-2 gene in the liver of adults occurs from both the paternal and the maternal alleles which may explain why circulating IGF-2 concentrations remain elevated throughout adult life.

IGF-2 exerts its biological effects by interacting with the IGF1R as well as the A form of the insulin receptor (IR-A). IGF-2 also binds to another receptor, that is specific for this particular IGF family member, identified as the IGF2R. The IGF2R is also a mannose-6-phosphate (M6P) receptor, similar to the M6P receptor that is responsible for the integration of lysosomal enzymes (which contain mannose-6-phosphate residues) into the lysosomes. Binding of IGF-2 to the IGF2R is responsible for clearance of IGF-2 from the circulation and does not contribute to IGF-2-mediated signal transduction. The IGF2R gene is located on chromosome 6q26 and is composed of 48 exons that encode a 2491 amino acid precursor protein. The IGF2R protein is a cation-independent mannose-6-phosphate receptor and therefore, is also referred to as the M6P/IGF2 receptor. In addition to IGF-2, the IGF2R has been shown to bind a diverse array of mannose-6-phosphate-containing proteins as well as several non-glycosylated proteins.

The initial observations that suggested the role of IGF-2 was most significant for fetal development only were obtained in knockout mouse studies. In these mice, fetal development was severely retarded yet following birth the mice grew normally and were fertile. Whereas in mice the level of IGF-2 falls following birth, in humans it does not. Studies in humans have shown that IGF-2 has a role in fetal growth and development by promoted formation of mesodermal germ layer. The level of IGF-2, in utero, is ten times higher than that of IGF-I. The growth effects of IGF-2 during fetal development are primarily exerted by its binding to, and activating, the IR-A form of the insulin receptor. Fetal actions of IGF-2 also involve activation of the IGF1R. In addition to its role in fetal development, IGF-2 is also an important regulator of placetal growth where it promotes nutrient transport, trophoblast invasion and proliferation and survival of cytotrophoblasts.

Post-natally IGF-2 exerts a potent angiogenic effect, central to its role in organ development and maintenance. The angiogenic effect of IGF-2 is the result of the growth factor inducing an up regulation of the expression of vascular endothelial growth factor, VEGF. IGF-2 has also been shown to exert growth promoting effects within the immune system. IGF-2 promotes granulocyte macrophage colony formation, stimulates the growth of B cells, and stimulates the growth of erythroid and myeloid precursor cells. Within specific organ systems IGF-2 exerts import growth and proliferative effects such as pancreatic β-cell proliferation and survival, development and maintenance of the musculoskeletal system, and development of bone. IGF-2, like insulin, exerts both growth factor functions and metabolic hormone regulating effects. These hormonal effects are most significant within adipose tissue, skeletal muscle and liver. Within the liver, IGF-2 actions result in the suppression of hepatic glucose output and increased glycogen synthesis. In adipose tissue and skeletal muscle, as well as several other peripheral tissues, IGF-2 induces glucose uptake and oxidation and increases synthesis of lipids and proteins.

In addition to its normal growth and metabolic functions, dysregulation of IGF-2 function has been associated with numerous pathologies, in particular in obesity and type 2 diabetes. Serum IGF-2 concentrations have been shown to increase in obesity and these levels correlate positively with BMI. The increased serum concentration of IGF-2 in obesity most likely represents an appropriate physiological response designed to promote energy storage in response to increased dietary supply. When overweight and obese individuals lose weight there is an associated decrease in total serum IGF-2 levels. In humans with normally low levels of serum IGF-2 there is an increased risk for weight gain and obesity. Although the mechanism by which the low levels of IGF-2 contribute to future weight gain is not clearly understood, it is an important prognostic indicator. Numerous studies have shown that IGF-2 is also dysregulated in diabetes. In type 2 diabetics, who are also obese, the levels of IGF-2 are even higher than in obese individuals that do not also exhibit insulin resistance typical of type 2 diabetes. Although the cause of the diabetes-related increase in IGF-2 is unknown, it believed to be primarily the result of increased adipose tissue secretion in response to hyperglycemia. The increases in serum IGF-2 seen in obese individuals has been shown to predispose these individuals to future development of insulin resistance and type 2 diabetes. Several studies have shown a strong correlation between obesity and cancer. In this context, the IGF systems are known to be causally linked to this phenomenon. The contribution to cancer development in obese patients, where IGF-2 levels are elevated, is thought to be exerted via IGF-2 binding to the IR-A form of the insulin receptor. When IGF-2 binds and activates this receptor, a set of signaling proteins, distinct from those activated by insulin binding, is activated that favor a mitogenic program increasing the likelihood for cancer.

Obesity in pregnant females has been shown to correlate with epigenetic changes in the IGF2 gene. These changes are reflected in a reduced level of methylation of the control region of the maternal IGF2 gene leading to increased expression of IGF-2 and increased IGF-2 concentrations in umbilical cord blood. The consequences of the altered maternal epigenome are evidenced by an adverse metabolic health of the fetus. Paternal obesity has also been associated with changes in the epigenome of the IGF2 gene. However, in the case of paternal obesity the reduced methylation is observed in the fetal IGF2 gene. Defects in imprinting at the IGF2 locus are seen in Beckwith-Wiedemann syndrome, BWS. As a result of the chromosomal alterations in BWS patients there is fetal overgrowth, organomegaly and an increased risk of developing tumours. Dysregulated, over-expression of IGF-2 in the BWS fetus is believed to account for the majority of the clinical features observed in this disease.

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Tumor Necrosis Factor-α (TNF-α)

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

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Tumor Necrosis Factor-β (TNF-β)

TNF-β (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-β is an inhibition of lipoprotein lipase present on the surface of vascular endothelial cells. The predominant site of TNF-β synthesis is T-lymphocytes, in particular the special class of T-cells called cytotoxic T-lymphocytes (CTL cells). The induction of TNF-β expression results from elevations in IL-2 as well as the interaction of antigen with T-cell receptors.

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Last modified: April 27, 2016