ADP-ribosylation factors 1 and 6 regulate Wnt/β-catenin signaling via control of LRP6 phosphorylation

W. Kim; S. Y. Kim; T. Kim; M. Kim; D. J. Bae; H. I. Choi; I. S. Kim; E. Jho

doi:10.1038/onc.2012.373

ADP-ribosylation factors 1 and 6 regulate Wnt/β-catenin signaling via control of LRP6 phosphorylation

W. Kim, S. Y. Kim, T. Kim, M. Kim, D. J. Bae, H. I. Choi, I. S. Kim, E. Jho

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

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)P 2 (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.

Original language	English
Pages (from-to)	3390-3396
Number of pages	7
Journal	Oncogene
Volume	32
Issue number	28
DOIs	https://doi.org/10.1038/onc.2012.373
Publication status	Published - 2013 Jul 11
Externally published	Yes

Keywords

ADP-ribosylation factor (Arf)
LRP6
Phosphatidylinositol 4,5 bisphosphate (PtdIns (4,5)P)
Signal transduction
Wnt

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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10.1038/onc.2012.373

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@article{0a6a880f3f464b998be2700cb3b58063,

title = "ADP-ribosylation factors 1 and 6 regulate Wnt/β-catenin signaling via control of LRP6 phosphorylation",

abstract = "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)P 2 (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.",

keywords = "ADP-ribosylation factor (Arf), LRP6, Phosphatidylinositol 4,5 bisphosphate (PtdIns (4,5)P), Signal transduction, Wnt",

author = "W. Kim and Kim, {S. Y.} and T. Kim and M. Kim and Bae, {D. J.} and Choi, {H. I.} and Kim, {I. S.} and E. Jho",

note = "Funding Information: This work was supported by grants from the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2006-2004046 and 2012R1A2A2A01012472 to E-HJ; 2010-0029206 to I-SK; 2011-0003980 to S-YK). WK, TK, and MK were supported by the Brain Korea 21 program.",

year = "2013",

month = jul,

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doi = "10.1038/onc.2012.373",

language = "English",

volume = "32",

pages = "3390--3396",

journal = "Oncogene",

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AU - Kim, W.

AU - Kim, S. Y.

AU - Kim, T.

AU - Kim, M.

AU - Bae, D. J.

AU - Choi, H. I.

AU - Kim, I. S.

AU - Jho, E.

N1 - Funding Information: This work was supported by grants from the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2006-2004046 and 2012R1A2A2A01012472 to E-HJ; 2010-0029206 to I-SK; 2011-0003980 to S-YK). WK, TK, and MK were supported by the Brain Korea 21 program.

PY - 2013/7/11

Y1 - 2013/7/11

N2 - 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)P 2 (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.

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ADP-ribosylation factors 1 and 6 regulate Wnt/β-catenin signaling via control of LRP6 phosphorylation

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Keywords

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