Structure-Function Analysis of the Human Insulin-like Growth Factor Binding Protein-4

Qin, Xu‐Jie; Strong, Donna D.; Baylink, David J.; Mohan, Subburaman

doi:10.1074/jbc.273.36.23509

Cited by 84 publications

(119 citation statements)

References 37 publications

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“…In addition, Kalus et al (10) purified two amino-terminal fragments of hIGFBP-5 (amino acid residues 1-94 and 40 -92) that exhibited similar affinity for IGF, both with 200-fold reduced affinity compared with wild-type. Imai et al (25) confirmed the importance of corresponding amino-terminal residues in IGFBP-3, and Qin et al (27) did the same for IGFBP-4. Furthermore, as amino acid residues 1-39 of hIGFBP-5 did not contribute to maintaining the complex, it was concluded that additional components required for IGF⅐IGFBP-5 complex stability would be derived from the carboxyl-terminal residues of IGFBPs (10).…”

Section: Discussionsupporting

confidence: 50%

BIAcore Analysis of Bovine Insulin-like Growth Factor (IGF)-binding Protein-2 Identifies Major IGF Binding Site Determinants in Both the Amino- and Carboxyl-terminal Domains

Carrick

Forbes

Wallace

2001

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 50%

BIAcore Analysis of Bovine Insulin-like Growth Factor (IGF)-binding Protein-2 Identifies Major IGF Binding Site Determinants in Both the Amino- and Carboxyl-terminal Domains

Carrick

Forbes

Wallace

2001

Journal of Biological Chemistry

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“…XIGFBP-4-H74P mutant was generated with a QuickChange Site-Directed Mutagenesis kit (Stratagene). Histagged human wild-type IGFBP-4 and mutant IGFBP-4-H74P (vectors provided by X. Qin) 8 were produced and purified with HisTrap HP Kit (Amersham). Fulllength Frz8, Frz8CRD and LRP6N were provided by X.…”

Section: Methodsmentioning

confidence: 99%

“…Treatment of P19CL6 cells with IGF-I and IGF-II also did not induce cardiomyocyte differentiation (data not shown). Furthermore, treatment with an IGFBP-4 mutant (IGFBP-4-H74P; His 74 replaced by Pro) 8 that is unable to bind IGFs induced cardiomyocyte differentiation of P19CL6 cells even more efficiently than wild-type IGFBP-4 (Fig. 1e).…”

mentioning

confidence: 99%

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Zhu

Shiojima

Ito

et al. 2008

Nature

207

165

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Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs) 1 . Although some of the actions of IGFBPs have been reported to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown 1,2 . Here we report a previously unknown function for IGFBP-4 as a cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor, Frizzled 8 (Frz8), and a Wnt co-receptor, lowdensity lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF-independent, the cardiogenic effect of IGFBP-4 was attenuated by IGFs through IGFBP-4 sequestration. IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling.The heart is the first organ to form during embryogenesis, and abnormalities in this process result in congenital heart diseases, the most common cause of birth defects in humans 3 . Molecules that mediate cardiogenesis are of particular interest because of their potential use for cardiac regeneration 4,5 . Previous studies have shown that soluble growth factors such as bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), Wnts and Wnt inhibitors mediate the tissue interactions that are crucial for cardiomyocyte specification 3,4 . We proposed that there might be additional soluble factors that modulate cardiac development and/or cardiomyocyte differentiation.P19CL6 cells differentiate into cardiomyocytes with high efficiency in the presence of 1% dimethylsulphoxide (DMSO) 6 . We cultured P19CL6 cells with culture media conditioned by various cell types in the absence of DMSO, and screened the cardiogenic activity of the conditioned media. The extent of cardiomyocyte differentiation was assessed by the immunostaining with MF20 monoclonal antibody that recognizes sarcomeric myosin heavy chain (MHC). Among the several cell types tested, culture media conditioned by a murine stromal cell line OP9 induced cardiomyocyte differentiation of P19CL6 cells without DMSO treatment (Fig. 1a, left and middle panels). Increased MF20-positive area was accompanied by the induction of cardiac marker genes such as aMHC, Nkx2.5 and GATA-4, and by the increased protein levels of cardiac troponin T (cTnT) (Fig. 1a, right panel). In contrast, culture media conditioned by COS7 cells, mouse embryonic fibroblasts, NIH3T3 cells, HeLa cells, END2 cells (visceral endoderm-like cells), neonatal rat cardiomyocytes and neonatal rat cardiac fibroblasts did not induce cardiomyocyte differentiation of P19CL6 cells in the absence of DMSO (Fig. 1a and data not shown). From these observations, we p...

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“…Approximately 2 ng of rPAPP-A contained in 293T culture medium was incubated for 16 h at 37°C in 2 mM CaCl 2 , 50 mM Tris, pH 7.5, with 10,000 cpm of purified 125 I-labeled IGFBP-4 (35) in the absence and presence of 5 nM IGF-II (Bachem), standard protease inhibitors, and 5 g/ml polyclonal anti-(PAPP-A/proMBP). 4 The total reaction volume was 25 l. Intact IG-FBP-4 and its proteolytic fragments were separated by reducing 15% SDS-PAGE and were visualized by autoradiography.…”

Section: Methodsmentioning

confidence: 99%

Expression of Recombinant Human Pregnancy-associated Plasma Protein-A and Identification of the Proform of Eosinophil Major Basic Protein as Its Physiological Inhibitor

Overgaard¹,

Haaning²,

Boldt³

et al. 2000

Journal of Biological Chemistry

169

160

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Structure-Function Analysis of the Human Insulin-like Growth Factor Binding Protein-4

Cited by 84 publications

References 37 publications

BIAcore Analysis of Bovine Insulin-like Growth Factor (IGF)-binding Protein-2 Identifies Major IGF Binding Site Determinants in Both the Amino- and Carboxyl-terminal Domains

BIAcore Analysis of Bovine Insulin-like Growth Factor (IGF)-binding Protein-2 Identifies Major IGF Binding Site Determinants in Both the Amino- and Carboxyl-terminal Domains

IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Expression of Recombinant Human Pregnancy-associated Plasma Protein-A and Identification of the Proform of Eosinophil Major Basic Protein as Its Physiological Inhibitor

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