THE ROLE OF THE INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS AND THE IGFBP PROTEASES IN MODULATING IGF ACTION

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The insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and the IGFBP proteases (BP-Pr) are involved in the regulation of somatic growth and cellular proliferation in vivo and in vitro. The growth effects of growth hormone are mediated primarily through the hepatic production of IGF-I. IGFs are potent mitogenic agents, and their actions are determined by the availability of free IGFs to interact with the IGF receptors. The levels of free IGFs in a system are modulated by the rate of IGF production, clearance, and degree of binding to the IGFBPs. The IGFBPs are a family of proteins that bind to IGFs with high affinity and specificity. IGFBPs not only regulate IGFs bioavailability but also seem to have their own receptors that mediate IGF-independent actions. IGFBPs are produced by a variety of different tissues, each of which has specific levels of several IGFBPs. In addition, several enzymes capable of proteolyzing IGFBPs have been identified. The cleavage of IGFBPs by BP-Pr has a key role in modulating free IGF and IGFBP levels and actions (Fig. 1). The authors thus propose two main mechanisms for the action of IGFBPs and their proteases to influence IGF action: (1) IGFBP binding to IGFs decrease the concentration of free IGFs available to interact with the IGF receptors and (2) cleavage of the IGFBPs into fragments with lower affinity to IGFs allows for increased IGF receptor activation.

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Address reprint requests to Pinchas Cohen, MD, Division of Endocrinology and Diabetes, Abramson Research Center, Room 410 D, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104

This work was supported by grants 1RO1DK 47591, 1RO1FD 1181, and 1RO1CA 58110 from the National Institutes of Health.

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From the Pediatric Endocrine Training Program, Division of Endocrinology (PC), Department of Pediatrics (PFC), University of Pennsylvania, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania