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[Insulin-like growth factor binding proteins] also abbr. IGBP or IBP. IGFBPs are found in various body fluids such as blood serum, amniotic fluid, and liquor. They are synthesized in the liver and are produced also by various tumor cell lines and cell types. Some cells produce and secrete some IGFBPs constitutively and the synthesis of some IGFBPs is regulated, among other things, by the two different IGF factors themselves. The two forms of IGF also appear to promote directly the proteolytic degradation of some IGFBPs (IGFBP4) into fragments that do not bind IGF, thus providing a mechanism by which each form of IGF may increase its own availability and/or activity in biological fluids.

IGFBPs are high affinity binding proteins for IGF. The major fraction of both types of IGF circulating in the blood are bound non-covalently to these carrier proteins, forming complexes of 140-150 kDa (large complex) and 40 kDa (small complex) which may be monomeric and oligomeric (IGFBP)n complexes. Some IGFBP/IGF complexes may contain additional complexed proteins. The formation of these complexes may be inhibited by glycosaminoglycans. Both types of IGF can be released from these complexes by treatment with acids, heparin, proteases, and plasmin.

IGF binding proteins modulate IGF activities by increasing their plasma half lives and by inhibiting or promoting the interactions of IGF with receptors on certain target cells. In addition these binding proteins provide a reservoir for IGF in pericellular spaces. Some IGFBPs also have stimulating effects in vitro and some may inhibit the growth of cells (see also: IDF-45). Some granulosa cell-derived IGFBPs appear to function as antigonadotropins at the level of the ovary. Small-cell lung cancer cells have been found to produce and release IGF binding proteins that differ from those found in liver and placenta. It has been suggested that they may function as mediators in the autocrine and/or paracrine growth regulation of IGF in these tumors.

IGFBPs are cysteine-rich proteins of which various molecular forms are known that may differ also in the extent of glycosylation. They have no sequence homology with the IGF receptors. The proteins display strong sequence homologies, suggesting that they are encoded by a closely related family of genes. The number (18) and position of the cysteine residues is conserved in almost all IGFBPs. There are some indications that IGFBPs can be phosphorylated and that phosphorylation also alters their biological activities. At present at least six different IGF binding proteins are known. They differ in their binding efficiencies.

IGFBP1 is a protein of 34 kDa (= BP-34, 34 k IGFBP). 25 kDa (IGF-BP25 [IGF binding protein 25]) and 28 kDa forms (25 k and 28 k IGFBP1) of this protein have been described also and probably arise by differences in glycosylation. The gene encoding this protein has a length of 5.2 kb and contains four exons. It maps to human chromosome 7p14-p12 at a distance of approximately 20 kb from the IGFBP3 gene. The transcription of the IGFBP1 gene is repressed by insulin while inhibitors of glucose uptake such as cytochalasin B enhance the synthesis of IGFBP1. Cortisol also increases plasma levels of IGFBP1 in humans. The synthesis of IGFBP1 by human hepatoma cells is enhanced by EGF. IGFBP1 has equal affinity for IGF-1 and IGF-2. Serine phosphorylation of IGFBP1 has been shown to alter its affinity for IGF-1 and IGF-2 and to modify its capacity to modulate cellular responses to the two forms of IGF.

The growth-inhibitory activities of IGFBP1 resemble those of another IGF-binding protein called IDF-45. BP-28 inhibits serum IGF bioactivity on cartilage in vitro. IGFBP1 has been shown also to be an inhibitor of IGF mitogenic activities for human breast cancer cells. BP-28 may be one of the IGF-1 inhibitors also observed in diabetic serum and may play a role in retarded growth and delayed puberty often seen in the adolescent diabetic. IGFBP1 enhances the mitogenic effect of IGF-1, but not that of IGF-2, in cultured human keratinocytes and fibroblasts.

In the human osteosarcoma cell line MG-63, IGFBP1 can form an IGF reservoir in the pericellular space surrounding the cells by forming complexes that are incapable of binding to the IGF receptors. These complexes can be dissolved by plasmin. The secretion of plasminogen activators by osteosarcoma cells and the availability of plasminogen in the extravascular tissues may provide a regulatory system in osteosarcoma cells in which pericellular plasmin affects the availability of the two forms of IGF to their membrane receptors.

The effect of IGFBP1 depends on its phosphorylation status; phosphorylated IGFBP1 inhibits IGF actions whereas the nonphosphorylated isoform is stimulatory. alpha2M has been shown to associate preferentially with the phosphorylated isoform of IGFBP1 anf thus indirectly to modify responses of cells to IGF. These complexes still bind IGF-1. alpha2M protects IGFBP1 from proteolysis and abrogates the inhibitory effect of phosphorylated IGFBP1 on IGF-1 stimulated 3T3-L1 cell proliferation (Westwood et al, 2001).

D'Ercole et al (1994) have studied transgenic mice overexpressing human IGFBP1 in the brain. The animals show brain growth retardation, which most likely results from IGFBP1 inhibition of growth-promoting actions stimulated by IGF. These mice should prove useful in defining IGF actions during postnatal brain maturation.

34 k IGFBP is identical with PP12 (Placental protein 12). The protein is secreted by the A673 human rhabdomyosarcoma cell line. The protein is known also as AFBP (amniotic fluid binding protein), Alpha-pregnancy-associated endometrial globulin, Growth hormone independent binding protein, Binding protein-28, Binding protein-26, and Binding protein-25. The 34 k IGFBP is the human counterpart of the rat protein BP-3A.

IGFBP1 has been described also as pregnancy-associated endometrial alpha-1-globulin, endometrial protein 14.

IGFBP1 is found predominantly in the placenta and the amniotic fluid. The predominant sites of IGFBP1 transcription in the human fetal kidney are those with most active differentiation. Elevated serum levels have been observed in patients with Laron-type dwarfism and Growth hormone deficiency. High serum levels of IGFBP1 are found in newborns and it has been suggested that this could be important in protecting them from hypoglycemia.

IGFBP2 (27 kDa, 24 kDa; 289 amino acids) is observed mainly in brain and liquor, showing complex patterns of gene expression during postnatal brain development. Elevated levels IGFBP2 have been observed in the serum of prostate cancer patients. IGFBP2 expression does not depend on Growth hormone. The gene maps to human chromosome 2q33-q34. It contains four exons and has a length of 32 kb. IGFBP2 has been shown to be secreted by intestinal epithelial cells and to capable of limiting the mitogenic activity of both exogenous and endogenous IGF by blocking the association of the growth factors with cell surface binding sites. IGFBP2 has been implicated also in myeloblast differentiation. It shows preferential affinity for IGF-2.

IGFBP3 (264 amino acids, 53 kDa; = BP-53) is the major IGF binding protein present in serum of humans and animals. It is also present in the alpha granules of platelets. IGFBP3 shows a similar affinity for IGF-1 and IGF-2. The mature protein is cysteine-rich and has a length of 264 amino acids. Its amino acid sequence is 33 % identical with that of IGFBP2. IGFBP3 is known also as Growth hormone dependent binding protein, acid stable subunit of the 140 K IGF complex, and Binding protein-29. The human gene has a length of 8.9 kb and contains 5 exons. It maps to chromosome 7p14-p12 in the vicinity of the IGFBP1 gene. Smaller fragments of IGFBP3 consisting of various C- or N-terminally truncated forms have been described also. A proteolytic enzyme specific for IGFBP3 has been isolated from serum of pregnant women.

The 140 kDa IGF binding protein complex in human serum consists of three subunits: an acid-labile, non-IGF-binding glycoprotein (alpha-subunit), IGFBP3 (beta-subunit), and IGF-1 or IGF-2 (gamma-subunit). Glycosaminoglycans have been shown to inhibit complex formation without affecting the binary complex. Since the ternary IGF-binding protein complex cannot cross the capillary barrier, a decrease in the affinity of the complex, mediated by circulating or cell-associated glycosaminoglycans, may be important in the passage of IGF and IGFBP3 to the tissues.

IGFBP3 inhibits follicle stimulating hormone. Markedly decreased levels of IGFBP3 are observed in patients with Growth hormone deficiencies (see also: Laron-type dwarfism), while markedly elevated levels are observed in patients with high levels of Growth hormone (acromegaly). In murine fibroblasts the synthesis of IGFBP3 is stimulated by mitogenic growth factors such as Bombesin, Vasopressin, PDGF, and EGF. In human skin fibroblasts the synthesis of IGFBP3 is stimulated by TGF-beta.

Stimulation by serum of dense cultures of murine 3T3 fibroblasts rapidly induces increased synthesis of a growth inhibitor identified as murine IGFBP3. Secretion of the factor is induced also by bFGF, PDGF, and insulin. DNA synthesis stimulated by bFGF is arrested when accumulation of mIGFBP3 is maximal, suggesting that the accumulation of mIGFBP3 may induce a feedback regulation of cell growth. An involvement of IGFBP3 in negative regulation of cell growth has been suggested by studies of transgenic fibroblasts lacking the type 1 IGF receptor and overexpressing this binding factor (see: IGF, subentry Transgenic /Knock-out/Antisense Studies).

IGFBP4 (237 amino acids) is the predominant IGF binding proteins expressed by human osteoblast-like cells. It is identical with a protein known as Colon cancer cell growth inhibitor. The human gene is on chromosome 17q12-q21 in the vicinity of the BRCA1 (hereditary breast-ovarian cancer gene) gene. This protein, known also as HT29-IGFBP (HT29 insulin-like growth factor binding protein), inhibits the growth of the human adenocarcinoma cell line HT29. IGFBP4 has been found to inhibit both basal and IGF mediated chick pelvic cartilage growth in vitro. IGFBP4 is subject to proteolysis by a IGFBP4-specific protease induced by IGF-2 that modifies IGFBP4 structure and function. This posttranslational regulation of IGFBP4 may provide a means for cooperative control of local cell growth by IGF-1 and IGF-2 (see: IGF).

IGFBP4 has been overexpressed in the malignant M12 prostate epithelial cell line to determine the effects on tumor formation and apoptosis. Overexpressing cells show reduced proliferation in response to IGF and inhibited colony growth in a soft agar colony formation assay. The cells overexpressing the binding protein also showed a delayed onset of tumor formation following transplantation into athymic nude mice. IGFBP2 protein levels have been found to be reduced in the conditioned medium of all IGFBP4 transfected cell cultures.

IGFBP5 is a protein of 23 kDa (252 amino acids) encoded by a gene on human chromosome 5. It is expressed highly in the kidney but is found also in other tissues. Human osteoblast-like bone cells in culture secrete several IGF-binding proteins, including IGFBP5 into the conditioned medium. It displays similar and relatively low affinities for IGF-1 and IGF-2. It enhances mitogenesis in the presence of IGF-1 or IGF-2 and also stimulates mitogenesis in the absence of exogenous or endogenous IGF.
For an antimicrobial peptide derived from IGFBP5 see also: AMP-IBP5 [antimicrobial peptide derived from IGFBP5].

Human IGFBP6 has a length of 216 amino acids (22.8 kDa) and is an O-glycosylated protein. It is abundant in cerebrospinal fluid and has a marked preferential binding affinity for IGF-2 over IGF-1. The gene maps to human chromosome 12. Levels of IGFBP6 (and also of IGFBP5) have been found to be increased in human breast cancer cells treated with estradiol and IGF-1 and may thus contribute to mitogenesis. Kato et al (2000) have shown that mac25 is a secreted tumor suppressor that binds to Activin A.

The cDNA, referred to as mac25, was identified also as a sequence expressed preferentially in senescent human mammary epithelial cells. The sequence shows 20-25 % identity with human IGFBP and binds IGF-1 and IGF-2 with low affinity. mac25 is now referred to as IGFBP7. mac25 mRNA is detectable in normal human tissues (breast, prostate, colon, and lung cancer cell lines).

Burger et al (1998) have shown that mac25 is identical also with a cDNA designated T1A12, the downregulated expression of which has been found to be associated with disease progression in breast carcinomas. IGFBP7 is identical with IGFBPrP1, TAF (tumor-derived adhesion factor), PSF (Prostacyclin stimulating factor), and Angiomodulin.

The designation IGFBP8 has been proposed by Kim et al (1997) for human CTGF following the observation that this factor possesses a conserved IGFBP motif (GCGCCXXC) and binds IGF with low affinity. A 29 kDa IGFBP has been found in human bone. This protein has a much higher affinity for IGF-2 than IGF-1 and potentiates the proliferative actions of IGF-2 on bone cells.

Copyright 2012 by H IBELGAUFTS. All rights reserved.



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