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). 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.
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
Weidong
W
Zhu
Ichiro
I
Shiojima
Yuzuru
Y
Ito
Zhi
Z
Li
Hiroyuki
H
Ikeda
Masashi
M
Yoshida
Atsuhiko T
AT
Naito
Jun-ichiro
J
Nishi
Hiroo
H
Ueno
Akihiro
A
Umezawa
Tohru
T
Minamino
Toshio
T
Nagai
Akira
A
Kikuchi
Makoto
M
Asashima
Issei
I
Komuro
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004625:Embryo, Nonmammalian / Q000196:embryology; D006321:Heart / Q000196:embryology*; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D029867:Xenopus Proteins; D014982:Xenopus laevis; D051176:beta Catenin / Q000378:metabolism
D018974:Insulin-Like Growth Factor Binding Protein 4; D026502:LDL-Receptor Related Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D043562:Receptors, G-Protein-Coupled; D013002:Somatomedins; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D029867:Xenopus Proteins; D051176:beta Catenin; C555476:Lrp6 protein, mouse; C555506:WNT3A protein, Xenopus; C555511:Wnt3a protein, mouse; C511610:Fzd8 protein, mouse