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

W Zhu, I Shiojima, Y Ito, Z Li, H Ikeda, M Yoshida… - Nature, 2008 - nature.com
W Zhu, I Shiojima, Y Ito, Z Li, H Ikeda, M Yoshida, AT Naito, J Nishi, H Ueno, A Umezawa
Nature, 2008nature.com
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 …
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.
nature.com