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

Weidong Zhu, Ichiro Shiojima, Yuzuru Ito, Zhi Li, Hiroyuki Ikeda, Masashi Yoshida, Atsuhiko T. Naito, Jun Ichiro Nishi, Hiroo Ueno, Akihiro Umezawa, Tohru Minamino, Toshio Nagai, Akira Kikuchi, Makoto Asashima, Issei Komuro

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Abstract

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.

Original languageEnglish
Pages (from-to)345-349
Number of pages5
JournalNature
Volume454
Issue number7202
DOIs
Publication statusPublished - Jul 17 2008
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Zhu, W., Shiojima, I., Ito, Y., Li, Z., Ikeda, H., Yoshida, M., Naito, A. T., Nishi, J. I., Ueno, H., Umezawa, A., Minamino, T., Nagai, T., Kikuchi, A., Asashima, M., & Komuro, I. (2008). IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature, 454(7202), 345-349. https://doi.org/10.1038/nature07027