The loss of glypican-3 induces alterations in Wnt signaling.
Loss-of-function mutations of the GPC3 gene are the cause of the human Simpson-Golabi-Behmel syndrome. Based on the overgrowth phenotype of the Simpson-Golabi-Behmel syndrome patients and the key role played by the insulin-like growth factor (IGF) signaling system in regulating embryonic growth, it was speculated that GPC3 regulates IGF signaling. In order to test the validity of this hypothesis, we mated GPC3 knockout mice with insulin receptor substrate-1 (IRS-1) nullizygous mice. We found that GPC3 regulates organism growth independent of IRS-1, suggesting that GPC3 does not modulate IGF signaling. Instead, we found that GPC3 knockout mice exhibit alterations in the Wnt signaling pathway, which is also associated with the regulation of cell proliferation. In particular, the loss of GPC3 led to the inhibition of the non-canonical Wnt/JNK signaling pathway, while concomitantly causing the activation of canonical Wnt/beta-catenin signaling. These in vivo findings were confirmed in vitro upon the ectopic overexpression of GPC3 in mesothelioma cells. In these cells, the GPC3-induced increase in JNK activity was associated with an enhanced response to Wnt5a. Most interestingly, the heparan sulfate chains of GPC3 were not required for its stimulatory activity on Wnt5a signaling and for the formation of GPC3-Wnt5a complexes. We propose that at least in some cell types GPC3 serves as a selective regulator of Wnt signaling, by potentiating non-canonical Wnt signaling, while inhibiting the canonical Wnt signaling pathway.
Song
Howard H
HH
Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Shi
Wen
W
Xiang
Yun-Yan
YY
Filmus
Jorge
J
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins
D017931:DNA Primers; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D036341:Intercellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D051153:Wnt Proteins