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

• Published in: Nature (London) 2008-07, Vol.454 (7202), p.345-349
• Main Authors: Komuro, Issei, Zhu, Weidong, Shiojima, Ichiro, Ito, Yuzuru, Li, Zhi, Ikeda, Hiroyuki, Yoshida, Masashi, Naito, Atsuhiko T, Nishi, Jun-ichiro, Ueno, Hiroo, Umezawa, Akihiro, Minamino, Tohru, Nagai, Toshio, Kikuchi, Akira, Asashima, Makoto
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - metabolism; Binding proteins; Binding sites; Biological and medical sciences; Cancer; Cardiology; Cell Differentiation; Cell Line, Tumor; Cells; Cellular signal transduction; Efficiency; Embryo, Nonmammalian - embryology; Fundamental and applied biological sciences. Psychology; Growth factors; Heart; Heart - embryology; Humanities and Social Sciences; Identification and classification; Insulin-Like Growth Factor Binding Protein 4 - metabolism; LDL-Receptor Related Proteins - metabolism; letter; Low Density Lipoprotein Receptor-Related Protein-6; Mice; Monoclonal antibodies; multidisciplinary; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Observations; Pediatric cardiology; Physiological aspects; Properties; Proteins; Receptors, G-Protein-Coupled - metabolism; Science; Signal Transduction; Somatomedins - metabolism; Vertebrates: cardiovascular system; Wnt Proteins - antagonists & inhibitors; Wnt Proteins - metabolism; Wnt3 Protein; Wnt3A Protein; Xenopus laevis; Xenopus Proteins
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature07027

Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs). 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. 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, low-density 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.