Insulin-Like Growth Factor (IGF) Binding Protein 2 Functions Coordinately with Receptor Protein Tyrosine Phosphatase β and the IGF-I Receptor To Regulate IGF-I-Stimulated Signaling

Shen, Xinchun; Xu, Gang; Maile, Laura A.; Wai, Christine; Rosen, Clifford J.; Clemmons, David R.

doi:10.1128/mcb.01011-12

Cited by 75 publications

(97 citation statements)

References 55 publications

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“…2), mediates the binding of IGFBP-2 to the cell surface receptor protein tyrosine phosphatase β (RPTPβ) (Fig. 3 left), an event leading to inhibition of the RPTPβ phosphatase activity (Shen et al 2012). An IGFBP-2 modulates IGFs bioavailability to their receptors, with involvement of specific IGFBP-2 protease.…”

Section: Ii)mentioning

confidence: 99%

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IGFBP-2 - taking the lead in growth, metabolism and cancer

Yau

Azar

Sabin

et al. 2015

J. Cell Commun. Signal.

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The activity of the Insulin-like Growth Factors (IGFs) ligands elicited via their receptors and transduced by various intracellular signal pathways is modulated by the IGF Binding Proteins (IGFBPs). Among all the IGFBPs, IGFBP-2 has been implicated in the regulation of IGF activity in most tissue and organs. Besides binding to IGFs in the circulation these IGF-regulatory activities of IGFBP-2 involve interactions with components of the extracellular matrix, cell surface proteoglycans and integrin receptors. In addition to these local peri-cellular activities, IGFBP-2 exerts other key functions within the nucleus, where IGFBP-2 directly or indirectly promotes transcriptional activation of specific genes. All of these IGFBP-2 activities, intrinsic or dependent on IGFs, contribute to its functional roles in growth/development, metabolism and malignancy as evidenced by studies in IGFBP-2 animal models and also by many in vitro studies. Finally, preclinical studies have demonstrated that IGFBP-2 administration can be beneficial in improving metabolic responses (inhibition of adipogenesis and enhanced insulin sensitivity), while blockade of IGFBP-2 appears to be an effective approach to inhibiting tumour growth and metastasis.

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Section: Ii)mentioning

confidence: 99%

“…3 IGF-dependent and IGF-independent action), including IGFBP-2 interactions at the cell surface (Russo et al 1995(Russo et al , 2005Shen et al 2012;Kawai et al 2011;DeMambro et al 2012) (Fig. 3) and intracellular / nuclear (Terrien et al 2005;Miyako et al 2009;Azar et al 2011Azar et al , 2014 (Fig.…”

Section: I)mentioning

confidence: 99%

IGFBP-2 - taking the lead in growth, metabolism and cancer

Yau

Azar

Sabin

et al. 2015

J. Cell Commun. Signal.

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“…However, we did not investigate the role of heparin-binding domain (HBD) in IGFBP-2 in our study. IGFBP-2 contains two HBDs, localized in the linker (HBD1) and C-terminal regions (HBD2), which are important for its binding to receptor protein tyrosine phosphatase β (RPTPβ) in regulating IGF-1 signalling (Shen et al 2012). In addition, integrin-mediated action of IGFBP-2 may contribute to the process of EPC homing to the injury site, which may be addressed through in vivo studies in the future.…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor Binding Protein-2 Promotes Adhesion of Endothelial Progenitor Cells to Endothelial Cells via Integrin α5β1

Zhang

Wang

et al. 2015

J Mol Neurosci

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The contribution of endothelial progenitor cells (EPCs) to new vessel formation has been studied in different physiological and pathological conditions for decades. As previously suggested, insulin-like growth factor binding protein-2 (IGFBP-2) may interact with integrins and promote cell migration. However, the role of IGFBP-2 in regulation of EPC functions remains largely unknown. In this present study, we found that overexpression of IGFBP-2 in human umbilical vein endothelial cells (HUVECs) promoted EPC-endothelial adhesion. Conversely, siRNA-mediated depletion of IGFBP-2 inhibited oxygen-glucose deprivation (OGD)-induced EPC-endothelial adhesion. Further, we demonstrated that the arginine-glycine-aspartic acid (RGD) motif in its C-domain is required for interaction with integrin α5β1. In addition, treatment with IGFBP-2 significantly enhanced incorporation of EPCs into tubule networks formed by HUVECs. Thus, our findings suggest that exogenous administration of IGFBP-2 may facilitate neovascularization and improve treatment of ischemic conditions.

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“…In this study, IGFBP2 was shown to bind to the proteoglycan receptor protein tyrosine phosphatase b via the linker-HBD independent of IGF1 binding. This binding in turn enhanced IGF1-stimulated vascular smooth muscle cell migration and proliferation (Shen et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Heparin-binding mechanism of the IGF2/IGF-binding protein 2 complex

Lund

Søndergaard

Conover

et al. 2014

Journal of Molecular Endocrinology

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IGF1 and IGF2 are potent stimulators of diverse cellular activities such as differentiation and mitosis. Six IGF-binding proteins (IGFBP1-IGFBP6) are primary regulators of IGF half-life and receptor availability. Generally, the binding of IGFBPs inhibits IGF receptor activation. However, it has been shown that IGFBP2 in complex with IGF2 (IGF2/IGFBP2) stimulates osteoblast function in vitro and increases skeletal mass in vivo. IGF2 binding to IGFBP2 greatly increases the affinity for 2-or 3-carbon O-sulfated glycosaminoglycans (GAGs), e.g. heparin and heparan sulfate, which is hypothesized to preferentially and specifically target the IGF2/IGFBP2 complex to the bone matrix. In order to obtain a more detailed understanding of the interactions between the IGF2/IGFBP2 complex and GAGs, we investigated heparin-binding properties of IGFBP2 and the IGF2/IGFBP2 complex in a quantitative manner. For this study, we mutated key positively charged residues within the two heparin-binding domains (HBDs) in IGFBP2 and in one potential HBD in IGF2. Using heparin affinity chromatography, we demonstrate that the two IGFBP2 HBDs contribute differentially to GAG binding in free IGFBP2 and the IGF2/IGFBP2 protein complex. Moreover, we identify a significant contribution from the HBD in IGF2 to the increased IGF2/IGFBP2 heparin affinity. Using molecular modeling, we present a novel model for the IGF2/IGFBP2 interaction with heparin where all three proposed HBDs constitute a positively charged and surface-exposed area that would serve to promote the increased heparin affinity of the complex compared with free intact IGFBP2. Key Words" IGF2/IGFBP2 complex " glycosaminoglycans " heparin affinity " ternary binding model

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Insulin-Like Growth Factor (IGF) Binding Protein 2 Functions Coordinately with Receptor Protein Tyrosine Phosphatase β and the IGF-I Receptor To Regulate IGF-I-Stimulated Signaling

Abstract: Insulin-like growth factor I (IGF-I) is a mitogen for vascular smooth muscle cells (VSMC) and has been implicated in the devel

Cited by 75 publications

References 55 publications

IGFBP-2 - taking the lead in growth, metabolism and cancer

IGFBP-2 - taking the lead in growth, metabolism and cancer

Insulin-Like Growth Factor Binding Protein-2 Promotes Adhesion of Endothelial Progenitor Cells to Endothelial Cells via Integrin α5β1

Heparin-binding mechanism of the IGF2/IGF-binding protein 2 complex

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