Structure, Dynamics and Heparin Binding of the C-terminal Domain of Insulin-like Growth Factor-binding Protein-2 (IGFBP-2)

Kuang, Zhihe; Yao, Shenggen; Keizer, David W; Wang, Chunxiao C; Bach, Leon Ashley; Forbes, Briony E.; Wallace, John C.; Norton, Raymond S.

doi:10.1016/j.jmb.2006.09.006

Cited by 51 publications

(55 citation statements)

References 70 publications

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“…19,[32][33][34] Membrane-associated IGFBP-2 stimulates or inhibits cell proliferation and migration through a direct binding to serum and extracellular matrix molecules, such as cell surface integrin receptors, proteoglycans, and heparin. [2][3][4][5]35 Meanwhile, a number of studies demonstrate that intracellular IGFBP-2 promotes cancer cell growth in various cell types.…”

Section: Discussionmentioning

confidence: 99%

Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma

Migita

Narita

Asaka

et al. 2010

The American Journal of Pathology

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Insulin-like growth factor (IGF) signaling plays a pivotal role in cell proliferation and mitogenesis. Secreted IGFbinding proteins (IGFBPs) are important modulators of IGF bioavailability; however, their intracellular functions remain elusive. We sought to assess the antiapoptotic properties of intracellular IGFBP-2 in lung adenocarcinomas. IGFBP-2 overexpression resulted in a decrease in procaspase-3 expression; however, it did not influence the phosphorylation status of either IGF receptor or its downstream targets, including Akt and extracellular signal-regulated kinase. Apoptosis induced by camptothecin was significantly inhibited by IGFBP-2 overexpression in NCI-H522 cells. Conversely, selective knockdown of IGFBP-2 using small-interfering RNA resulted in an increase in procaspase-3 expression and sensitization to camptothecin-induced apoptosis in NCI-H522 cells. LY294002, an inhibitor of phosphatidylinositol 3-kinase, caused a decrease in IGFBP-2 levels and enhanced apoptosis in combination with camptothecin. Immunohistochemistry demonstrated that intracellular IGFBP-2 was highly expressed in lung adenocarcinomas compared with normal epithelium. Intracellular IGFBP-2 and procaspase-3 were expressed in a mutually exclusive manner. These findings suggest that intracellular IGFBP-2 regulates caspase-3 expression and contributes to the inhibitory effect on apoptosis independent of IGF. IGFBP-2, therefore, may offer a novel therapeutic target and serve as an antiapoptotic biomarker for lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma

Migita

Narita

Asaka

et al. 2010

The American Journal of Pathology

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“…This region is also involved with integrin binding via the RGD domain additional pH-dependent heparin-binding site, reported as HBD2 (Fig. 2), has been located within the carboxylterminal region and thyroglobulin type-1 domain of IGFBP-2 (Kuang et al 2006). …”

Section: Ii)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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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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“…IGF2-binding residues of IGFBP2 are highlighted in orange. IGF2 residues involved in IGF1R (turquoise) and IGF2R (olive green) binding are also highlighted (Butler et al 1998, Clemmons 2001, Kuang et al 2006, Williams et al 2007, Brown et al 2008. Disulfide bridges identified in this study are shown with black lines.…”

Section: Protein Expression Purification and Analysismentioning

confidence: 92%

“…Homology structural modeling MODELLER v.9.10 was used for the generation of a threedimensional structural model of the IGF2/IGFBP2 complex using the structures of human IGF1 in complex with human IGFBP4 N-and C-terminal domains (PDB ID: 2DSR), C-terminal domain of human IGFBP2 (PDB ID: 2H7T), and IGF2 (PDB ID: 1IGL) as templates (Torres et al 1995, Eswar et al 2006, Kuang et al 2006, Sitar et al 2006. Clustal W sequence alignments of template sequences, and murine IGFBP2 (ID P47877) and human IGF2 (ID P01344), respectively, were used to generate 50 models.…”

Section: Heparin Affinity Chromatographymentioning

confidence: 99%

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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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Structure, Dynamics and Heparin Binding of the C-terminal Domain of Insulin-like Growth Factor-binding Protein-2 (IGFBP-2)

Cited by 51 publications

References 70 publications

Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma

Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma

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

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

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