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 / IU School of Medicine / mking@medicine.indstate.edu
Last modified: Thursday, 10-May-01 10:12:34