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      The role of insulin-like growth factor binding proteins.

      Neuroendocrinology
      Animals, Endopeptidases, metabolism, Humans, Insulin-Like Growth Factor Binding Proteins, classification, physiology, Signal Transduction, Somatomedins

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          Abstract

          Insulin-like growth factors (IGFs) are fundamental cell regulators with an evolutionary conserved role synchronising tissue growth, development and function according to metabolic conditions. Although structurally very similar to insulin, the IGFs act in a very different way as cell regulators. Whereas insulin is stored in a specific gland and released when needed, the IGFs are stored outside of cells with soluble binding proteins. A very complex system of six IGF binding proteins, each of which exists in various modified states and interacts with other proteins, provides a sophisticated system for conferring specificity to provide a finely tuned system for local regulation at the tissue level.

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          Most cited references31

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          The CCN family of angiogenic regulators: the integrin connection.

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            Insulin-like growth factor binding protein 1 stimulates cell migration and binds to the alpha 5 beta 1 integrin by means of its Arg-Gly-Asp sequence.

            Insulin-like growth factor (IGF)-binding protein 1 (IGFBP-1) contains an Arg-Gly-Asp (RGD) integrin recognition sequence. In vitro mutagenesis was used to alter this RGD sequence to Trp-Gly-Asp (WGD). Migration of Chinese hamster ovary (CHO) cells expressing the wild-type protein was more than 3-fold greater in 48 hr compared with cells expressing the WGD mutant form of IGFBP-1. Similarly, wild-type IGFBP-1 added to the media of control CHO cells stimulated migration 2-fold compared with the WGD protein. A synthetic RGD-containing peptide, when added to the medium with wild-type IGFBP-1, blocked the effect of IGFBP-1 on cell migration. The addition of IGF-I to the culture medium had no effect on the migration of cells expressing IGFBP-1 or vector alone. Affinity chromatography of 125I-labeled CHO cell membrane proteins, using IGFBP-1 coupled to agarose, identified the alpha 5 beta 1 integrin (fibronectin receptor) as the only cell surface molecule capable of binding IGFBP-1 in an RGD-dependent manner. Furthermore, wild-type IGFBP-1, but not the WGD mutant form, could be coprecipitated from CHO cells with an antibody directed against the alpha 5 integrin subunit. These studies demonstrate that IGFBP-1 stimulates CHO cell migration and binds to the alpha 5 beta 1 integrin receptor, both by an RGD-dependent mechanism. The effect of IGFBP-1 on migration is independent of IGF-I and is probably mediated through the alpha 5 beta 1 integrin.
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              Direct functional interactions between insulin-like growth factor-binding protein-3 and retinoid X receptor-alpha regulate transcriptional signaling and apoptosis.

              Insulin-like growth factor-binding protein (IGFBP)-3 regulates apoptosis in an IGF-independent fashion and has been shown to localize to nuclei. We cloned the nuclear receptor retinoid X receptor-alpha(RXR-alpha) as an IGFBP-3 protein partner in a yeast two-hybrid screen. Multiple methodologies showed that IGFBP-3 and RXR-alpha bind each other within the nucleus. IGFBP-3-induced apoptosis was abolished in RXR-alpha-knockout cells. IGFBP-3 and RXR ligands were additive in inducing apoptosis in prostate cancer cells. IGFBP-3 enhanced RXR response element and inhibited RARE signaling. Thus, RXR-alpha-IGFBP-3 interaction leads to modulation of the transcriptional activity of RXR-alpha and is essential for mediating the effects of IGFBP-3 on apoptosis.
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                Author and article information

                Journal
                17047378
                10.1159/000095523

                Chemistry
                Animals,Endopeptidases,metabolism,Humans,Insulin-Like Growth Factor Binding Proteins,classification,physiology,Signal Transduction,Somatomedins

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