The carboxy-terminal domain of IGF-binding protein-5 inhibits heparin binding to a site in the central domain

Song, Hyuk; Shand, John H.; Beattie, James; Flint, David; Allan, Gordon J.

doi:10.1677/jme.0.0260229

Cited by 20 publications

(16 citation statements)

References 32 publications

(51 reference statements)

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“…HBD peptide derived from IGFBP-2 did not inhibit angiogenesis indicating that angiogenesis inhibition is specific to the heparin-binding site of IGFBP-5. IGFBP-5 has three putative heparin-binding sites: two overlapping sites in the linker domain ( 132 VKKDRRKKL 140 ) and one in the C-terminal region ( 205 YKRKQCKP 212 ); however, only the C-terminal heparin-binding site is functional15. This might explain why VEGF-A expression and tumor growth were inhibited only in 2774 cells stably expressing the C-terminus of IGFBP-5.…”

Section: Discussionmentioning

confidence: 99%

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The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis

Hwang

Cho

Lee

et al. 2016

Sci Rep

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Insulin-like growth factor-binding protein 5 (IGFBP-5) plays a role in cell growth, differentiation, and apoptosis. In this study, we found that IGFBP5 was markedly downregulated in ovarian cancer tissue. We investigated the functional significance of IGFBP-5 as a tumor suppressor. To determine functional regions of IGFBP-5, truncation mutants were prepared and were studied the effect on tumor growth. Expression of C-terminal region of IGFBP-5 significantly decreased tumor growth in an ovarian cancer xenograft. A peptide derived from the C-terminus of IGFBP-5 (BP5-C) was synthesized to evaluate the minimal amino acid motif that retained anti-tumorigenic activity and its effect on angiogenesis was studied. BP5-C peptide decreased the expression of VEGF-A and MMP-9, phosphorylation of Akt and ERK, and NF-kB activity, and inhibited angiogenesis in in vitro and ex vivo systems. Furthermore, BP5-C peptide significantly decreased tumor weight and angiogenesis in both ovarian cancer orthotopic xenograft and patient-derived xenograft mice. These results suggest that the C-terminus of IGFBP-5 exerts anti-cancer activity by inhibiting angiogenesis via regulation of the Akt/ERK and NF-kB–VEGF/MMP-9 signaling pathway, and might be considered as a novel angiogenesis inhibitor for the treatment of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

“…The C-terminal domain also has a nuclear localization signal and a heparin-binding site. The L-domain also contains a heparin-binding site, but this site has been reported to be nonfunctional15. The heparin-binding domain consists of the consensus amino acid sequence XBBBXXBX or XBBXBX (B: basic amino acid, X: undefined amino acid).…”

mentioning

confidence: 99%

The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis

Hwang

Cho

Lee

et al. 2016

Sci Rep

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“…This domain has been shown to interact with extracellular matrix proteins, such as fibronectin, thrombospondin-1, osteopontin and vitronectin (Akkiprik et al, 2008). In addition, IGFBP5 contains a total of three heparin-binding motifs in the C-terminal and L domains (Song et al, 2001). These motifs in IGFBP5 bind to glycosaminoglycans in the extracellular matrix and can be blocked by heparin (Song et al, 2001).…”

Section: Igfbp5 In Osteosarcomamentioning

confidence: 99%

“…In addition, IGFBP5 contains a total of three heparin-binding motifs in the C-terminal and L domains (Song et al, 2001). These motifs in IGFBP5 bind to glycosaminoglycans in the extracellular matrix and can be blocked by heparin (Song et al, 2001). The ability of IGFBP5 to bind to extracellular matrix proteins may modulate cell-cell and cell-matrix interactions.…”

Section: Igfbp5 In Osteosarcomamentioning

confidence: 99%

Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma

et al. 2011

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Osteosarcoma (OS) is the most common primary malignancy of bone. There is a critical need to identify the events that lead to the poorly understood mechanism of OS development and metastasis. The goal of this investigation is to identify and characterize a novel marker of OS progression. We have established and characterized a highly metastatic OS subline that is derived from the less metastatic human MG63 line through serial passages in nude mice via intratibial injections. Microarray analysis of the parental MG63, the highly metastatic MG63.2 subline, as well as the corresponding primary tumors and pulmonary metastases revealed insulin-like growth factor binding protein 5 (IGFBP5) to be one of the significantly downregulated genes in the metastatic subline. Confirmatory quantitative RT-PCR on 20 genes of interest demonstrated IGFBP5 to be the most differentially expressed and was therefore chosen to be one of the genes for further investigation. Adenoviral mediated overexpression and knockdown of IGFBP5 in the MG63 and MG63.2 cell lines, as well as other OS lines (143B and MNNG/HOS) that are independent of our MG63 lines, were employed to examine the role of IGFBP5. We found that overexpression of IGFBP5 inhibited in vitro cell proliferation, migration and invasion of OS cells. Additionally, IGFBP5 overexpression promoted apoptosis and cell cycle arrest in the G1 phase. In an orthotopic xenograft animal model, overexpression of IGFBP5 inhibited OS tumor growth and pulmonary metastases. Conversely, siRNA-mediated knockdown of IGFBP5 promoted OS tumor growth and pulmonary metastases in vivo. Immunohistochemical staining of patient-matched primary and metastatic OS samples demonstrated decreased IGFBP5 expression in the metastases. These results suggest 1) a role for IGFBP5 as a novel marker that has an important role in the pathogenesis of OS, and 2) that the loss of IGFBP5 function may contribute to more metastatic phenotypes in OS.

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“…Investigation at the molecular level of the interaction between heparin and IGFBP-5 has identified the region lying between residues 201 and 218 as the major heparin binding domain (Arai et al 1996) and an extensive site-directed mutagenesis study within this region of the protein has indicated the importance of specific basic amino acid residues in binding to heparin (Parker et al 1996). Sequence analysis of IGFBPs has also indicated the presence of an 'S type' heparin binding domain in the central region of some IGFBPs (Hodgkinson et al 1994) and further work from our group has shown that there is also a central heparin binding site in IGFBP-5, involving the amino acids Arg136 and Arg137 (Song et al 2001).…”

Section: Introductionmentioning

confidence: 98%

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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The carboxy-terminal domain of IGF-binding protein-5 inhibits heparin binding to a site in the central domain

Cited by 20 publications

References 32 publications

The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis

The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis

Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma

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

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