The Type V Transforming Growth Factor β Receptor Is the Putative Insulin-like Growth Factor-binding Protein 3 Receptor

Abstract

Insulin-like growth factor-binding protein 3 (IGFBP-3) has been shown to inhibit cell growth by IGF-dependent and -independent mechanisms. The putative cell-surface IGFBP-3 receptor that mediates the IGF-independent growth inhibition has not been identified. Here we show that recombinant human IGFBP-3 inhibits 125 Itransforming growth factor (TGF)-␤ 1 binding to the type V TGF-␤ receptor (M r 400,000) in mink lung epithelial cells. We also demonstrate that the ϳ400-kDa

Insulin-like growth factor binding protein-3 (IGFBP-3): Novel ligands mediate unexpected functions

“…IGFBP-3 association with the surface of cells has been recognized for over two decades (Martin, et al 1992) but the original characterization of its binding sites as functional receptors (Oh, et al 1993) was not fully substantiated. A large cell-surface protein termed the type V transforming growth factor-β receptor (TβRV) was later shown to bind IGFBP-3, but again its putative role in IGFBP-3 signaling was not well established (Leal, et al 1997). This protein was subsequently determined to be identical to the low density lipoprotein receptor-related protein LRP1, also known as the α2-macroglobulin receptor, and its mediation of IGFBP-3 growth-inhibitory signaling was said to involve the dephosphorylation of insulin receptor substrate-2 (IRS-2) (Huang, et al 2004).…”

Interactions of High Affinity Insulin-like Growth Factor-binding Proteins with the Type V Transforming Growth Factor-β Receptor in Mink Lung Epithelial Cells

“…These IGF-independent actions of high affinity IGFBPs are believed to be mediated by specific cell-surface receptors or membrane proteins (6, 16 -18). The IGFBP-3 receptor, which mediates the IGF-independent growth inhibitory response, has been recently identified as the type V TGF-␤ receptor (T␤R-V) (19).…”

A Pentacosapeptide (CKS-25) Homologous to Retroviral Envelope Proteins Possesses a Transforming Growth Factor-β Activity

“…It is thus possible that the growth inhibitory response stimulated by CKS-25 protein conjugates could be mediated by any of the known receptors or some combination. The type V TGF-␤ receptor was suggested as a candidate by the finding that insulin-like growth factor protein 3, which also contains a WCVD motif (19), is a specific ligand for the type V TGF-␤ receptor and exhibits partial TGF-␤ agonist activity (growth inhibition but not transcription activation) (10). Like the CKS-25 protein conjugates, insulin-like growth factor protein 3 exerts a maximum of ϳ50% inhibition of DNA synthesis (10).…”

“…For RNA analysis, cells grown on 12-well cluster dishes were treated with 10 M CKS-25, 10 M CKS-25-BSA, 10 M CKS-25-CA conjugate, or TGF-␤ 1 (0.25 and 2.5 pM) at 37°C for 2.5 h in 0.1% fetal calf serum. The extraction of RNA and Northern blot analysis were carried out as described previously (10).…”

“…[methyl- 3 The assay of [methyl-3 H]thymidine incorporation into cellular DNA was carried out in triplicate as described previously (10). For RNA analysis, cells grown on 12-well cluster dishes were treated with 10 M CKS-25, 10 M CKS-25-BSA, 10 M CKS-25-CA conjugate, or TGF-␤ 1 (0.25 and 2.5 pM) at 37°C for 2.5 h in 0.1% fetal calf serum.…”