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

Ho Seong Kim, Srinivasa R. Nagalla, Youngman Oh, Elizabeth Wilson, Charles Roberts, Ronald (Ron) Rosenfeld

Research output: Contribution to journalArticle

265 Citations (Scopus)

Abstract

The insulin-like growth factor (IGF) binding proteins (IGFBPs) modulate the actions of the insulin-like growth factors in endocrine, paracrine, and autocrine settings. Additionally, some IGFBPs appear to exhibit biological effects that are IGF independent. The six high-affinity IG-FBPs that have been characterized to date exhibit 40-60% amino acid sequence identity overall, with the most conserved sequences in their NH2 and COOH termini. We have recently demonstrated that the product of the mnc25/IGFBP-7 gene, which shows significant conservation in the NH2 terminus, including an 'IGFBP motif' (GCGCCXXC), exhibits low-affinity IGF binding. The closely related mammalian genes connective tissue growth factor (CTGF) gene, nor, and cyr61 encode secreted proteins that also contain the conserved sequences and IGFBP motifs in their NH2 termini. To ascertain if these genes, along with mac25/IGFBP-7, encode a family of low-affinity IGFBPs, we assessed the IGF binding characteristics of recombinant human CTGF (rhCTGF). The ability of baculovirus-synthesized rhCTGF to bind IGFs was demonstrated by Western ligand blotting, affinity crosslinking, and competitive affinity binding assays using 125I-labeled IGF-I or IGF-II and unlabeled IGFs. CTGF, like mac25/IGFBP-7, specifically binds IGFs, although with relatively low affinity. On the basis of these data, we propose that CTGF represents another member of the IGFBP family (IG-FBP-8) and that the CTGF gene, mac2S/IGFBP-7, nov, and cyr61 are members of a family of low-affinity IGFBP genes. These genes, along with those encoding the high-affinity IGFBPs 1-6, together constitute an IGFBP superfamily whose products function in IGF-dependent or IGF-independent modes to regulate normal and neoplastic cell growth.

Original languageEnglish (US)
Pages (from-to)12981-12986
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number24
DOIs
StatePublished - Nov 25 1997

Fingerprint

Connective Tissue Growth Factor
Insulin-Like Growth Factor Binding Proteins
Somatomedins
Genes
Amino Acid Motifs
Conserved Sequence
Insulin-Like Growth Factor Binding Protein 6
Insulin-Like Growth Factor Binding Protein 1
Aptitude
Insulin-Like Growth Factor II
Competitive Binding
Baculoviridae
Insulin-Like Growth Factor I
Amino Acid Sequence
Western Blotting
Ligands
insulin-like growth factor binding protein-related protein 1

Keywords

  • Peptide hormones
  • Serum Inducible factors
  • Transforming growth factor β

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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. / Kim, Ho Seong; Nagalla, Srinivasa R.; Oh, Youngman; Wilson, Elizabeth; Roberts, Charles; Rosenfeld, Ronald (Ron).

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 24, 25.11.1997, p. 12981-12986.

Research output: Contribution to journalArticle

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abstract = "The insulin-like growth factor (IGF) binding proteins (IGFBPs) modulate the actions of the insulin-like growth factors in endocrine, paracrine, and autocrine settings. Additionally, some IGFBPs appear to exhibit biological effects that are IGF independent. The six high-affinity IG-FBPs that have been characterized to date exhibit 40-60{\%} amino acid sequence identity overall, with the most conserved sequences in their NH2 and COOH termini. We have recently demonstrated that the product of the mnc25/IGFBP-7 gene, which shows significant conservation in the NH2 terminus, including an 'IGFBP motif' (GCGCCXXC), exhibits low-affinity IGF binding. The closely related mammalian genes connective tissue growth factor (CTGF) gene, nor, and cyr61 encode secreted proteins that also contain the conserved sequences and IGFBP motifs in their NH2 termini. To ascertain if these genes, along with mac25/IGFBP-7, encode a family of low-affinity IGFBPs, we assessed the IGF binding characteristics of recombinant human CTGF (rhCTGF). The ability of baculovirus-synthesized rhCTGF to bind IGFs was demonstrated by Western ligand blotting, affinity crosslinking, and competitive affinity binding assays using 125I-labeled IGF-I or IGF-II and unlabeled IGFs. CTGF, like mac25/IGFBP-7, specifically binds IGFs, although with relatively low affinity. On the basis of these data, we propose that CTGF represents another member of the IGFBP family (IG-FBP-8) and that the CTGF gene, mac2S/IGFBP-7, nov, and cyr61 are members of a family of low-affinity IGFBP genes. These genes, along with those encoding the high-affinity IGFBPs 1-6, together constitute an IGFBP superfamily whose products function in IGF-dependent or IGF-independent modes to regulate normal and neoplastic cell growth.",
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