ADP-ribosylation factors 1 and 6 regulate Wnt/β-catenin signaling via control of LRP6 phosphorylation.
It has been shown that inhibition of GTPase-activating protein of ADP-ribosylation factor (Arf), ArfGAP, with a small molecule (QS11) results in synergistic activation of Wnt/β-catenin signaling. However, the role of Arf in Wnt/β-catenin signaling has not yet been elucidated. Here, we show that activation of Arf is essential for Wnt/β-catenin signaling. The level of the active form of Arf (Arf-GTP) transiently increased in the presence of Wnt, and this induction event was abrogated by blocking the interaction between Wnt and Frizzled (Fzd). In addition, knockdown of Fzds, Dvls or LRP6 blocked the Wnt-mediated activation of Arf. Consistently, depletion of Arf led to inhibition of Wnt-mediated membrane PtdIns (4,5)P2 (phosphatidylinositol 4, 5-bisphosphate) synthesis and LRP6 phosphorylation. Overall, our data suggest that transient activation of Arf modulates LRP6 phosphorylation for the transduction of Wnt/β-catenin signaling.
Department of Life Science, The University of Seoul, Seoul, Korea.
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D020823:ADP-Ribosylation Factor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051157:Frizzled Receptors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D051379:Mice; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000096:biosynthesis; D010766:Phosphorylation; D015398:Signal Transduction; D013997:Time Factors; D060509:Wnt3A Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D000089982:ADP-Ribosylation Factor 6; D051157:Frizzled Receptors; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D019269:Phosphatidylinositol 4,5-Diphosphate; D060509:Wnt3A Protein; D051176:beta Catenin; D020823:ADP-Ribosylation Factor 1; D020727:ADP-Ribosylation Factors