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In biologic fluids, insulinlike growth factors (IGF-I and IGF-11) are bound to high-afinity insulinlike growth factor binding proteins (IGFBPs), of which seven have now been identified (IGFBPs 1–7). In a variety of biologic fluids, severalIGFBPs undergoproteolytic degradation. Such degradationcan leadto increasedIGF bioavailabilityat the cell su+ace, facilitating receptor interactions. HeYein,recent dataidentifying several IGFBP-degrading proteinases and their effects on IGF bioactivity is reviewed,andhow IGFBPproteolysis is regulatedbyIGFs and IGFBPs, as well as how IGFBP cleavageanalysisprovides insights r into the structure and function of IGFBPs, is explored. (Trends Endocrinol Metab 1997;8:299–306). 01997, Elsevier Science Inc.

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Dr. Fowlkes is at the Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536-0284 USA.

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Table 1. The known varieties of insulinlike growth factor binding proteins and their functions IGFBP

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Figurel. Schematic representation of insulinlike growth factor binding protein (IGFBP)-3. Human IGFBP-3 is divided into three distinct domains: an N-terminal domain [amino acids (aa) l-87], a nonhomologous midregion (shaded; aa 88-183), anda C-terminal domain (aa 184–264). Cleavage sites are denoted by ~forthe following proteinases: a, plasmin; b,trypsin; c, prostate–specific antigen (PSA); d, pregnant and nonpregnant serum; e, thrombin; f, matrix metalloproteinases (MMP)-l; g, MMP-2; andh, MMP-3. From Wood et al. (1988), Fowlkes et al. (1994), Fielderet al. (1994), Booth et al. (1996). Heparin-binding domains are underlined. From Fowlkeset al. (1996).

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2. Hypothetical model showing how insulinlike growth factor binding protein (IGFBP) proteolysis regulates IGF bioavailability at the cell surface. (1) The IGFBP-3–IGF complex is attacked by an IGFBP-3–degrading proteinase, cleaving IGFBP-3 into N- and C-terminal fragments. IGFs bound to low-affinity fragments of IGFBP-3 are then released to interact with cell-surface type 1 IGF receptors (5). (2) C-terminal fragments of IGFBP-3, which contain a heparin-binding domain, may inactivate the IGFBP-4-degrading proteinase. (3) The IGFBP4–degrading proteinase can also be inhibited by unsaturated IGFBP-3, as well as IGFBP-5 and IGFBP-6; however, the presence of IGFs reverses the inhibitory effects of IGFBP-3 on the IGFBP-4-degrading proteinase. (4) Active IGFBP-4-degrading proteinase will cleave IGFBP-4 in the midregion of the molecule, reducing the affinity of IGFBP-4, and allowing for IGF–type 1 IGF receptor interactions to occur (5).

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Andress DL, Loop SM, Zapf J, Kiefer MC: insulin-like 1993. Carboxy-truncated growth factor binding protein-5 stimulates mitogenesis in osteoblast-like cells. Biochem Biophys Res Commun 195:25–30. Angelloz-Nicoud P, Binoux M: 1995. Autocrine regulation of cell proliferation by the insulin-like growth factor (IGF) and IGFbinding protein-3 protease system in a human prostate cancer cell line (PC-3). Endocrinology 136:5485–5492. Arai T, Arai A, Busby WH Jr, Clemmons DR: 1994. Glycosaminoglycans inhibit degradation of insulin-like growth factor-binding protein-5. Endocrinology 135:2358-2363. Bach LA, Rechler MM: 1995. Insulin-like growth factor binding proteins. Diabetes Rev 3:38-61. Baxter RC, Bayne ML, Cascieri MA: 1992. Structural determinants for binary and ternary complex formation between insulinlike growth factor-I (IGF-1) and IGF binding protein-3. J Biol Chem 267:60–65.

Braulke T, Claussen M, Saftig P, et al.: 1995. Proteolysis of IGFBPs by cathepsin D–deficient mice. Prog Growth Factor Res 6:265– 271.

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Andress DL, Birnbaum RS: 1992. Human osteoblast-derived insulin-like growth factor (IGF) binding protein-5 stimulates osteoblast mitogenesis and potentates IGF action. J Biol Chem 267:22,467–22,472.

Booth BA, Bees M, Bar RS: 1996. IGFBP-3 proteolysis by plasmin, thrombin, serum: heparin binding, IGF binding, and structure of fragments. Am J Physiol 271:E465– E470.

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References

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Acknowledgements

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by human fibroblasts and the mechanisms that regulate their secretion. J Biol Chem 267:1 1,949-11,956. Campbell PG, Novak JF, Yanosick TB, McMaster JH: 1992. Involvement of the plasmin system in dissociation of the insulinlike growth factor-binding protein complex. Endocrinology 130:1401-1412. Chernausek SD, Smith CE, Duffin KL, Busby WH, Wright G, Clemmons DR: 1995. Proteolytic cleavage of insulin-like growth factor binding protein 4 (IGFBP-4): localization of cleavage site to non-homologous region of native IGFBP-4. J Biol Chem 270: 11,377-11,382. Cohen P, Graves HCB, Peehl DM, Kamarei M, Giudice LC, Rosenfeld RG: 1992. Prostatespecific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. J Clin Endocrinol Metab 75:1046-1053. Cohen P, Peehl DM, Graves HCD, Rosenfeld RG: 1994. Biological effects of prostate specific antigen (PSA) as an IGF binding protein-3 (IGFBP-3) protease. J Endocrinol 14: 407-415. Cohen P, Noveral JP,Bhala A, Nunn SE, Herrick DJ, Grunstein MM: 1995. Leukotriene D4 facilitates airway smooth muscle cell proliferation via modulation of the IGF axis. Am J Physiol 269:L151–LI 57. Conover CA: 1995. Insulin-like growth factor binding protein proteolysis in bone cell models. Prog Growth Factor Res 6:301– 309.

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Fowlkes JL, Enghild JJ, Suzuki K. Nagase H: 1994a. Matrix metalloproteinases degrade insulin-like growth factor-binding protein-3 in dermal fibroblast cultures. J Biol Chem 269:25,742-25,746.

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Fowlkes JL, Suzuki K, Nagase H, Thailkill KM: 1994b. Proteolysis of insulin-like growth factor binding protein-3 during rat pregnancy: role for matrix metalloproteinases. Endocrinology 135:2810–2813.

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Fowlkes JL, Thrailkill KM, Serra DM, Suzuki K, Nagase H: 1995b. Matrix metalloproteinases as insulin-like growth factor binding protein-degrading proteinases. Prog Growth Factor Res 6:255-263. Fowlkes JL, Thrailkill KM, Carlos-George N, Rosenberg CK, Serra DM: 1997. Heparinbinding highly basic regions within the thyroglobulin type-1 repeat of insulin-like growth factor binding proteins (IGFBPs) -3, -5 and -6 inhibit IGFBP-4 degradation. Endocrinology 138:2280-2285.

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Vincenzo Papa, Angela Costantino, and Antonino Belfiore

It is commonly believedthat the insulin receptor mainly mediatesthe metabolic effectsof insulin, whereasthe closelyrelatedIGF-I Teceptoris considereda major factor for the regulation of cell proliferation. Experimental and epidemiological evidenceindicates,howeve~ that insulin and insulin receptorsmayplay an important role in breastcancez This article reviewsevidenceindicating that (a) insulin receptors are overexpressedin human b~eastcancec (b) insulin stimulates growth in breast cancer cells, (c) cells transected with human insulin ~eceptor mayacquire a ligand-dependenttransformedphenotype,and (d) breast cancer is associated with insulin resistance and hypetinsulinemia. Thesefindings mayopen newpossibilities in breastcancerprevention, prognosis assessment,and therapy. (Trends Endocrinol Metab 1997; 8:306–312). 01997, Elsevier Science Inc.

Rajah R, Nunn SE, Hernck DJ, GrunsteinMM, Cohen P: 1996. Leukotriene D4 induces MMP-1, which functions as an IGFBP protease in human airway smooth muscle cells. Am J Physiol 271:L1014-L1O22.

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Rechler MM: 1993. Insulin-like growth factor binding proteins. Vitam Horm 47:1-1 14. Rechler MM: 1995. Non-receptor-binding proteins for insulin-like growth factors and other cytokines: modulators of peptide action. In Weintraub BD, ed. Molecular Endocrinology: Basic Concepts and Clinical Correlations. New York, Raven Press, pp 155-180. Salahifar H, Baxter RC, Martin JL: 1997. Insulin-like growth factor binding protein (IGFBP)-3 protease activity secreted by MCF-7 breast cancer cells: inhibition by IGFs does not require IGF-IGFBP interaction. Endocrinology 138:1683–1690. Thrailkill KM, Quarles LD, Nagase H, Suzuki K, Serra DM, Fowlkes JL: 1995. Characterization of insulin-like growth factor-binding protein-5-degrading proteases produced throughout murine osteoblast differentiation. Endocrinology 136:3527-3533. Wood WI, Cachianes G, Henzel WJ, et al.: 1988. Cloning and expression of the growth hormone-dependent insulin-like growth factor-binding protein. Endocrinol 2:1 176-1185.

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Vincenzo Papa, Angela Costantino, and Antonino Belfiore are at the Istituto di Medicina Interna, Malattie Endocrine e del Metabolism, Cattedra di Endocrinologia, University of Catania, ospedale Garibaldi, 95128, Catania, Italy. Vincenzo Papa is currently at the Medical Department, SPA, Lavinaio (Catania), 95020, Italy.

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