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Recommendations for Nomenclature of the Insulin-Like Growth Factor Binding Protein Superfamily

Kolling Institute of Medical Research (R.C.B.), St. Leonards, New South Wales 2065, Australia; INSERM U-142, Hopital Sainte-Antoine (M.A.B.), Paris, France; Department of Medicine, Division of Endocrinology, University of North Carolina School of Medicine (D.R.C.), Chapel Hill, North Carolina 27599-7170; Endocrine Research Unit, Mayo Clinic (C.A.C.), Rochester, Minnesota 55905-0001; Division of Endocrinology, Sophia Children’s Hospital (S.L.S.D.), Rotterdam, Netherlands; Department of Surgery, Bristol Royal Infirmary (J.M.P.H.) Bristol, United Kingdom; Department of Medicine, Loma Linda University (S.M.) Loma Linda, California 92357-0001; Department of Pediatrics, Oregon Health Sciences University (Y.O., R.G.R.) Portland, Oregon 97201

Address correspondence and requests for reprints to: Ron G. Rosenfeld, M.D., Department of Pediatrics, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201. E-mail: rosenfer{at}ohsu.edu

	Introduction

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THE NOMENCLATURE for the insulin-like growth factor (IGF) binding proteins (IGFBP) was established at the 2nd and 3rd International IGF Symposia (1, 2). The IGFBPs constitute a family of six structurally related proteins that bind IGF peptides with high affinity (typical K_d in the 10^-10 to 10^-11 M range). They share an overall protein sequence identity of approximately 50% and contain 16–18 conserved cysteines in the NH₂- and COOH-terminal regions (3). Recently, the predicted protein product of the mac25 complementary DNA (4) was shown to be structurally related to the IGFBPs, especially in the amino-terminal region, where 11–12 of the 12 cysteines found in IGFBPs 1–6 are conserved (5). The protein was synthesized in a baculovirus expression system (5), found to be identical to previously described tumor-derived adhesion factor (6) and prostacyclin-stimulating factor (7), and to bind IGF-I, IGF-II, and insulin, but with relatively low affinity. It was, accordingly, provisionally named IGFBP-7 (5, 8).

A closely related family of genes (CCN) has been identified, encoding immediate early gene products, connective tissue growth factor, and cyr61, as well as a putative avian proto-oncogene, nov (CCN stands for connective tissue growth factor, Cyr61/Cef10, nephroblastoma overexpressed gene) (9). The amino-terminal regions of the predicted proteins are structurally homologous to the classical IGFBPs, with conservation of the cysteine-rich region. As is the case with mac25/TAF/PSF/IGFBP-7, the carboxyl terminus of IGFBPs 1–6 is not conserved in these three proteins. The protein product of the CTGF gene has been synthesized in a baculovirus system and has been found to bind IGF-I and IGF-II with low affinity (10). This protein was provisionally named IGFBP-8, and, on the basis of their structural homologies, the protein products of nov and cyr61 were provisionally named IGFBP-9 and IGFBP-10, respectively (10).

The structural relationship of these proteins, especially in the amino-terminal regions is clear and suggests that the classical six IGFBPs and these low-affinity IGF binders are members of an IGFBP superfamily. This superfamily consists of at least three gene families: 1) the IGFBPs, 2) the protein product of the mac25 gene, and 3) members of the CCN family. In light of their relatively low affinities for IGF peptides, it is recommended that they not be named IGF binding proteins, but, rather, be termed insulin-like growth factor binding protein-related proteins (IGFBP-rP), until further elucidation of their molecular, biochemical, and physiological relationships to the classical IGFBPs (see Table 1).

Received March 20, 1998.

Revised May 7, 1998.

Accepted May 19, 1998.

	References

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7. Yamauchi T, Umeda F, Masakado M, Isaji M, Mizushima S, Nawata H. 1994 Purification and molecular cloning of prostacyclin-stimulating factor serum-free conditioned medium of human diploid fibroblast cells. Biochem J. 303:591–598.
8. Rosenfeld RG, Oh Y. 1998 The blind men and the elephant: A parable for the study of IGFBPs. Endocrinology. 139:5–7.[Free Full Text]
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10. Kim H-S, Nagalla SR, Oh Y, Wilson E, Roberts Jr CT, Rosenfeld RG. 1997 Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc Natl Acad Sci USA. 94:12981–12986.[Abstract/Free Full Text]

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