A unique receptor-independent mechanism by which insulinlike growth factor I regulates the availability of insulinlike growth factor binding proteins in normal and transformed human fibroblasts.

Conover, Cheryl A.

doi:10.1172/jci115441

Cited by 71 publications

(44 citation statements)

References 54 publications

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“…The data in the current manuscript may suggest an additional interpretation of the molecular relationships in the IGF-IGFBPheparin axis whereby heparin or heparan sulphate, and certain other GAGs, are occupied with unliganded IGFBP-3 and -5 and that free IGF in the local environment may displace IGFBP-3 and -5 from ECM as IGF-IGFBP complexes. Indeed it has been shown previously that addition of IGF-I to cultures of human fibroblasts will release IGFBP-3 into conditioned medium (Conover 1991, Martin et al 1992. Although to our knowledge no equivalent data existed to demonstrate IGF-dependent release of IGFBP-5 in a cell culture model, we were able to demonstrate that IGF-I and -II could displace endogenous IGFBP-5 from monolayers of the mouse mammary epithelial cell line HC11 (Fig.…”

Section: Discussionsupporting

confidence: 48%

Molecular recognition characteristics in the insulin-like growth factor (IGF)-insulin-like growth factor binding protein -3/5 (IGFBP-3/5) heparin axis

Beattie¹,

Phillips²,

Shand³

et al. 2005

Journal of Molecular Endocrinology

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Insulin-like growth factor binding proteins (IGFBPs) -3 and -5 are known to interact with various components of the extracellular matrix (ECM; e.g. heparin and heparan sulphate) and this interaction is believed to affect the affinity of both IGFBP species for their cognate ligands -IGF-I and -II. There is little detail on the nature of the molecular complex formed between ECM components, IGFBPs and IGFs although the glycosaminoglycan (GAG) heparin has been reported to reduce the affinity of IGFBP-5 for IGF-I. In order to investigate this phenomenon further, we have undertaken an extensive surface plasmon resonance based biosensor study to report the affinity of IGFBP-3 and -5 for binding heparin (22 and 7 nM respectively). We have also shown that pre-complexation of IGFBP with IGF-I and -II inhibits the subsequent association of IGFBP with heparin and conversely that heparin complexation of IGFBP-3 and -5 inhibits IGFBP binding to biosensor surfaces containing immobilised IGF-I. In addition we have used both IGF-I and heparin coated biosensor surfaces in an attempt to build ternary IGF-IGFBP-heparin complexes in order to gain some insight into the nature of inhibition by heparin of IGFI-IGFBP complex formation. Our data lead us to conclude that the inhibition by heparin is partly competitive in nature, and that ternary complexes of IGF-IGFBP-heparin are either unable to form, or only form unstable transient complexes. The potential biological significance of our data is highlighted by the demonstration that IGF-I and IGF-II can displace endogenous IGFBP-5 from monolayer cultures of the mouse mammary epithelial cell line HC11.

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Section: Discussionsupporting

confidence: 48%

Molecular recognition characteristics in the insulin-like growth factor (IGF)-insulin-like growth factor binding protein -3/5 (IGFBP-3/5) heparin axis

Beattie¹,

Phillips²,

Shand³

et al. 2005

Journal of Molecular Endocrinology

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“…Proliferation studies using normal adult human osteoblasts were performed as described previously by our laboratory (33,34). In brief, adult human osteoblastic cells were plated in 24-well plates and grown for either 1 d or for 10 d. Cells were washed and changed to serum-free medium without or with 10 nM of IGF-II, IGFBP-2, or the combination.…”

Section: Methodsmentioning

confidence: 99%

Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults.

et al. 1998

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Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in bone mass during adult life. Despite the rarity of HCAO, understanding the mediator(s) of the skeletal disease is of great interest. The IGFs-I and -II have potent anabolic effects on bone, and alterations in the IGFs and/or IGF-binding proteins (IGFBPs) could be responsible for the increase in bone formation in this disorder. Thus, we assayed sera from seven cases of HCAO for IGF-I, IGF-II, IGF-IIE (an IGF-II precursor), and IGFBPs. The distribution of the serum IGFs and IGFBPs between their ternary ( ‫ف‬ 150 kD) and binary ( ‫ف‬ 50 kD) complexes was also determined to assess IGF bioavailability.HCAO patients had normal serum levels of IGF-I and -II, but had markedly elevated levels of IGF-IIE. Of the IGFBPs, an increase in IGFBP-2 was unique to these patients and was not found in control hepatitis C or hepatitis B patients. IGF-I and -II in sera from patients with HCAO were carried, as in the case of sera from control subjects, bound to IGFBP-3 in the ‫ف‬ 150-kD complex, which is retained in the circulation. However, IGF-IIE was predominantly in the ‫ف‬ 50-kD complex in association with IGFBP-2; this complex can cross the capillary barrier and access target tissues. In vitro, we found that IGF-II enhanced by over threefold IGFBP-2 binding to extracellular matrix produced by human osteoblasts and that in an extracellular matrix-rich environment, the IGF-II/IGFBP-2 complex was as effective as IGF-II alone in stimulating human osteoblast proliferation. Thus, IGFBP-2 may facilitate the targeting of IGFs, and in particular IGF-IIE, to skeletal tissue in HCAO patients, with a subsequent stimulation by IGFs of osteoblast function. Our findings in HCAO suggest a possible means to increase bone mass in patients with osteoporosis. (

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“…Although its precise biological function is unknown, IGFBP-4 has been implicated as a potent inhibitor ofIGF action in bone and in other systems (8,22,26,(30)(31)(32). Recently, we reported that, in contrast to an increase in IGFBP-3, treatment of normal human fibroblasts and human osteoblast-like cells with IGF-I or IGF-II led to a marked reduction in the levels of 24-kD IGFBP-4 detected in the cell-conditioned medium (25,33). An IGF-induced decrease in human fibroblast-derived IGFBP-4 was also described by Neely and Rosenfeld (34) and Clemmons et al (27).…”

Section: Introductionmentioning

confidence: 99%

Posttranslational regulation of insulin-like growth factor binding protein-4 in normal and transformed human fibroblasts. Insulin-like growth factor dependence and biological studies.

Conover¹,

Kiefer²,

Zapf³

1993

J. Clin. Invest.

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170

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Insulin-like growth factor binding protein4 (IGFBP4) is a 24-26-kD protein expressed by a variety of cell types in vivo and in vitro. Treatment of normal adult human fibroblasts with 10 nM insulin-like growth factor II (IGF-II) for 24 h resulted in an 85% decrease in endogenous IGFBP4, as assessed by Western ligand blot analysis of the conditioned medium. Incubation of human fibroblast-conditioned medium (HFCM) with IGF-II under cell-free conditions led to a similar loss of IGFBP4. This posttranslationally regulated decrease in IGFBP-4 appeared to be due to a protease in HFCM: (a) It could be prevented with specific protease inhibitors or incubation at 40C; (b) proteolysis of recombinant human (rh) IGFBP-4 required HFCM; (c) immunoblotting and radiolabeling confirmed cleavage of IGFBP4 into 18-and 14-kD IGFBP4 fragments. The protease was specific for IGFBP4, and was strictly dependent on IGFs for activation. IGF-II was the most effective of the natural and mutant IGFs tested, inducing complete hydrolysis of rhIGFBP4 at a molar ratio of 0.25:1 (IGF/IGFBP4). Simian virus 40-transformed adult human fibroblasts also expressed IGFBP4 and IGFBP4 protease, as well as an inhibitor of IGFBP4 proteolysis. In biological studies, intact rhIGFBP4 potently inhibited IGF-I-stimulated [3HIaminoisobutyric acid uptake, whereas proteolyzed rhIGFBP-4 had no inhibitory effect. In conclusion, these data provide evidence for a novel IGF-dependent IGFBP4-specific protease that modifies IGFBP4 structure and function, and indicate a preferential role for IGF-II in its activation. Posttranslational regulation of IGFBP4 may provide a means for cooperative control of local cell growth by IGF-I and IGF-II.

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A unique receptor-independent mechanism by which insulinlike growth factor I regulates the availability of insulinlike growth factor binding proteins in normal and transformed human fibroblasts.

Cited by 71 publications

References 54 publications

Molecular recognition characteristics in the insulin-like growth factor (IGF)-insulin-like growth factor binding protein -3/5 (IGFBP-3/5) heparin axis

Molecular recognition characteristics in the insulin-like growth factor (IGF)-insulin-like growth factor binding protein -3/5 (IGFBP-3/5) heparin axis

Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults.

Posttranslational regulation of insulin-like growth factor binding protein-4 in normal and transformed human fibroblasts. Insulin-like growth factor dependence and biological studies.

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