Capping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A

Abstract Hedgehog (Hh) signaling plays a pivotal role in animal development and its deregulation in humans causes birth defects and several types of cancer. Protein Kinase A (PKA) modulates Hh signaling activity through phosphorylating the transcription factor Cubitus interruptus (Ci) and G protein...

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Autores principales:	Ping Chen, Zizhang Zhou, Xia Yao, Shu Pang, Meijing Liu, Weirong Jiang, Jin Jiang, Qing Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6118751f44e64d58a3434e85b641125e
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spelling	oai:doaj.org-article:6118751f44e64d58a3434e85b641125e2021-12-02T16:06:01ZCapping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A10.1038/s41598-017-03165-22045-2322https://doaj.org/article/6118751f44e64d58a3434e85b641125e2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03165-2https://doaj.org/toc/2045-2322Abstract Hedgehog (Hh) signaling plays a pivotal role in animal development and its deregulation in humans causes birth defects and several types of cancer. Protein Kinase A (PKA) modulates Hh signaling activity through phosphorylating the transcription factor Cubitus interruptus (Ci) and G protein coupled receptor (GPCR) family protein Smoothened (Smo) in Drosophila, but how PKA activity is regulated remains elusive. Here, we identify a novel regulator of the Hh pathway, the capping-enzyme mRNA-cap, which positively regulates Hh signaling activity through modulating PKA activity. We provide genetic and biochemical evidence that mRNA-cap inhibits PKA kinase activity to promote Hh signaling. Interestingly, regulation of Hh signaling by mRNA-cap depends on its cytoplasmic capping-enzyme activity. In addition, we show that the mammalian homolog of mRNA-cap, RNGTT, can replace mRNA-cap to play the same function in the Drosophila Hh pathway and that knockdown of Rngtt in cultured mammalian cells compromised Shh pathway activity, suggesting that RNGTT is functionally conserved. Our study makes an unexpected link between the mRNA capping machinery and the Hh signaling pathway, unveils a new facet of Hh signaling regulation, and reveals a potential drug target for modulating Hh signaling activity.Ping ChenZizhang ZhouXia YaoShu PangMeijing LiuWeirong JiangJin JiangQing ZhangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ping Chen Zizhang Zhou Xia Yao Shu Pang Meijing Liu Weirong Jiang Jin Jiang Qing Zhang Capping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A
description	Abstract Hedgehog (Hh) signaling plays a pivotal role in animal development and its deregulation in humans causes birth defects and several types of cancer. Protein Kinase A (PKA) modulates Hh signaling activity through phosphorylating the transcription factor Cubitus interruptus (Ci) and G protein coupled receptor (GPCR) family protein Smoothened (Smo) in Drosophila, but how PKA activity is regulated remains elusive. Here, we identify a novel regulator of the Hh pathway, the capping-enzyme mRNA-cap, which positively regulates Hh signaling activity through modulating PKA activity. We provide genetic and biochemical evidence that mRNA-cap inhibits PKA kinase activity to promote Hh signaling. Interestingly, regulation of Hh signaling by mRNA-cap depends on its cytoplasmic capping-enzyme activity. In addition, we show that the mammalian homolog of mRNA-cap, RNGTT, can replace mRNA-cap to play the same function in the Drosophila Hh pathway and that knockdown of Rngtt in cultured mammalian cells compromised Shh pathway activity, suggesting that RNGTT is functionally conserved. Our study makes an unexpected link between the mRNA capping machinery and the Hh signaling pathway, unveils a new facet of Hh signaling regulation, and reveals a potential drug target for modulating Hh signaling activity.
format	article
author	Ping Chen Zizhang Zhou Xia Yao Shu Pang Meijing Liu Weirong Jiang Jin Jiang Qing Zhang
author_facet	Ping Chen Zizhang Zhou Xia Yao Shu Pang Meijing Liu Weirong Jiang Jin Jiang Qing Zhang
author_sort	Ping Chen
title	Capping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A
title_short	Capping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A
title_full	Capping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A
title_fullStr	Capping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A
title_full_unstemmed	Capping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A
title_sort	capping enzyme mrna-cap/rngtt regulates hedgehog pathway activity by antagonizing protein kinase a
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/6118751f44e64d58a3434e85b641125e
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Capping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A

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