The Insulin-like Growth Factor Binding Protein Superfamily: New Perspectives

Abstract

The insulin-like growth factor (IGF) binding proteins (IGFBPs) were initially identified as carrier proteins for IGF-I and IGF-II in a variety of biologic fluids. Their presumed function was to protect IGF peptides from degradation and clearance, increase the half-life of the IGFs, and deliver them to appropriate tissue receptors. The concept of IGFBPs as simple carrier proteins has been complicated, however, by a number of observations: 1) the six IGFBPs vary in their tissue expression and their regulation by other hormones and growth factors; 2) the IGFBPs are subjected to proteolytic degradation, thereby altering their affinities for the IGFs; 3) IGFBP-3 and IGFBP-5, in addition to binding IGFs, also can associate with an acid-labile subunit, thereby increasing further the half-life of the IGFs; 4) in addition to modifying the access of IGF peptides to IGF and insulin receptors, several of the IGFBPs may be capable of increasing IGF action; 5) some of the IGFBPs may be capable of IGF-independent regulation of cell growth; 6) some of the IGFBPs are associated with cell membranes or possibly with membrane receptors; and 7) some of the IGFBPs have nuclear recognition sites and may be found within the nucleus. Additionally, a number of cDNAs identified recently have been found to encode proteins that bind IGFs, but with substantially lower affinities than is the case with IGFBPs. The N-terminal regions of the predicted proteins are structurally homologous to the classic IGFBPs, with conservation of the cysteine-rich region. These observations suggest that these low-affinity binders are members of an IGFBP superfamily, capable of regulating cell growth by both IGF-dependent and IGF-independent mechanisms. insulin-like growth factor, insulin-like growth factor binding proteins.

Inhibition of the Insulin-like Growth Factor-1 Receptor (IGF1R) Tyrosine Kinase as a Novel Cancer Therapy Approach

“…The physiological activities of the IGFs are regulated in part by their physical association with the IGF-binding proteins (IGFBPs), a six-member family of secreted proteins (IGFBP1−6) that bind both IGF1 and IGF2 with high (although varied) affinities. , The IGFBPs can either potentiate or inhibit IGF function, in part by maintaining a reservoir of IGFs in the circulation (a function mainly of IGFBP3) and by transporting IGFs from the circulation to peripheral tissues (IGFBP1, -2, and -4). In addition, the IGFBPs mediate IGF-independent biological effects that will not be discussed in this review (for a detailed discussion and specific example of this role for the IGFBPs, see refs and ).…”

Asymmetric growth-limiting development of the female conceptus

“…This supports the view that IGF2 may act as a fetal demand signal to the placenta, as previously demonstrated by gene deletion studies in mouse ( 65 , 66 ) and is consistent with growth-promoting actions of IGF2 at mid-gestation through the placenta ( 24 , 67 , 68 ). Growth-promoting effects of IGFs are regulated by binding proteins (IGFBPs), which transport IGFs in plasma, increase their half-life, and regulate the availability of free IGFs ( 69 ). We found lower cord serum total IGFBP levels in females at mid-gestation, potentially a compensatory mechanism to increase IGF availability in response to lower circulating IGF2.…”

Insulin-Like Growth Factor-1 and Its Binding Proteins, IGFBP-1 and IGFBP-3, in Adolescents with Type-1 Diabetes mellitus and Microalbuminuria

“…The changes in IGFBP-1 may alter the bioactivity of free IGF-1 [34] , and hence could signifi cantly contribute to the origin of diabetic complications. A lower IGF-1 level may be caused by enhanced clearance due to abnormal regulation of IGFBPs [35] .…”