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

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, 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.