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- Title
IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis.
- Authors
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; Komuro, Issei
- 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.
- Subjects
INSULIN-like growth factor-binding proteins; GROWTH factors; HEART cells; HEART development regulation; HEART cytology; WNT proteins
- Publication
Nature, 2008, Vol 454, Issue 7202, p345
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature07027