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The Insulin-Like Growth Factor-Binding Protein (IGFBP) Superfamily
Vivian Hwa, Youngman Oh and Ron G. Rosenfeld Endocr. Rev. 1999 20: 761-787, doi: 10.1210/er.20.6.761

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0163-769X/99/$03.00/0 Endocrine Reviews 20(6): 761–787 Copyright © 1999 by The Endocrine Society Printed in U.S.A.

The Insulin-Like Growth Factor-Binding Protein (IGFBP) Superfamily*
VIVIAN HWA, YOUNGMAN OH,
AND

RON G. ROSENFELD

Department of Pediatrics, Oregon Health Sciences University, Portland, Oregon 97201

I. Introduction A. Concept of an IGFBP superfamilyB. Superfamily nomenclature II. IGFBP Family A. Structure of IGFBPs B. Correlations between structure and function C. Biological functions of IGFBPs D. Genomics of IGFBPs III. Mac25 A. IGFBP-rP1 (Mac25/TAF/PSF) IV. CCN Family A. IGFBP-rP2 (CTGF) B. IGFBP-rP3 (NovH) C. IGFBP-rP4 (Cyr61) D. New members V. L56 A. IGFBP-rP5 (L56/HtrA) VI. ESM-1 A. IGFBP-rP6 (endothelial specific molecule-1) VII.Structural Relationships Within the IGFBP Superfamily A. Protein domains (modules) B. Gene structure and correlation with protein domains VIII. Functional Relationships Within the IGFBP Superfamily A. IGF binding B. Insulin binding C. IGF/insulin-independent actions IX. Evolutionary Relationships Within the IGFBP Superfamily A. N-terminal domains B. C-terminal domains C. Evolutionary models X. SummaryI. Introduction

HE insulin-like growth factor (IGF) system (Fig. 1) is well defined, with profound effects on the growth and differentiation of normal and malignant cells. The established
Address reprint requests to: Ron G. Rosenfeld, M.D., Department of Pediatrics, Oregon Health Sciences University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97201 USA. E-mail: rosenfer@ ohsu.edu* Supported by NIH Grants CA-58110 and DK-51513 and by US Army Grants DAMD 17–96-1–2604 and DAMD 17–97-1–7204.

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components of the IGF system include IGFs (IGF-I and IGFII), type I and type II IGF receptors, IGF-binding proteins (IGFBPs), and IGFBP proteases. IGF-I and IGF-II, which are structurally similar to insulin, are two highly homologous small hormone peptides of approximately 7 kDamolecular mass. First identified in 1957, they were originally named sulfation factors (1), nonsuppressible insulin-like activity (2), and multiplication-stimulating activity (3). They were renamed somatomedins (4) and subsequently IGFs (5). IGFs are ubiquitously expressed and are important mitogens that affect cell growth and metabolism. In addition to endocrine effects exerted by circulatingIGFs (6, 7), locally produced IGFs exert paracrine, as well as autocrine, effects on cell proliferation (8 –10). The IGFs interact with specific cell surface receptors, designated type I and type II IGF receptors, and can also interact with the insulin receptor. The mitogenic effects of IGF are mediated mainly through interactions with the type I IGF receptor, which, like the insulin receptor, is areceptor with tyrosine kinase activity. The type II IGF receptor is structurally distinct, binds primarily IGF-II, but also serves as a receptor for mannose-6-phosphate-containing ligands (11). The role(s) of the type II receptor in mediating IGF action is less well defined (12). In biological fluids, IGFs are normally bound to IGFBPs. There are, at present, six well characterized mammalian IGFBPs,designated IGFBP-1 through -6. IGFBPs have higher 10 10 m) than do the type I IGF affinities for IGFs (kd receptors (kd 10 8–10 9 m). Therefore, IGFBPs act not only as carriers of IGFs, thereby prolonging the half-life of the IGFs, but also function as modulators of IGF availability and activity (see review in Ref. 10). In the past several years, knowledge of the biological roles of IGFBPs has...