Role of Lipid Metabolism in Smoothened Derepression in Hedgehog Signaling

Yavari, Amir; Nagaraj, Raghavendra; Owusu-Ansah, Edward; Folick, Andrew; Ngo, Kathy T.; Hillman, R. Tyler; Call, Gerald B.; Rohatgi, Rajat; Scott, Matthew P.; Banerjee, Utpal

doi:10.1016/j.devcel.2010.06.007

Cited by 94 publications

(121 citation statements)

References 40 publications

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“…Differential regulation of the enzymes probably results in production of different pools of the same lipid within the cell, emphasizing the importance of identifying factors that control specific pools. Indeed, genetic interactions indicate that Hedgehog relieves Patched inhibition of Drosophila PI4KIIIa, suggesting that PI4KIIIa activity is regulated (Yavari et al, 2010). PI4KIIIa also promotes FGF signaling in zebrafish (Ma et al, 2009), Hippo signaling in flies (Yan et al, 2011) and MAPK signaling in yeast (Garrenton et al, 2010).…”

Section: D123mentioning

confidence: 99%

“…PI4Ks are crucial for cell homeostasis, yet only a handful of studies address their functions in multicellular organisms (Brill et al, 2000;Burgess et al, 2012;Khuong et al, 2010;Ma et al, 2009;Polevoy et al, 2009;Raghu et al, 2009;Simons et al, 2009;Yan et al, 2011;Yavari et al, 2010). A recent report examining mouse PI4KIIIa revealed transient localization of PI4KIIIa to the PM (Nakatsu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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PI4KIIIα is required for cortical integrity and cell polarity during Drosophila oogenesis

Tan

Burgess

et al. 2014

Journal of Cell Science

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There was an error published in J. Cell Sci. 127, 954-966.The synonym for l(1)3Ah 21 was incorrectly identified as zw2 c21 on pages 955 and 963 of this article. The correct synonym is zw2 123 , not to be confused with the allele generated in this study, which is PI4KIIIa D123 .Accordingly, on page 955, the sentence 'Like PI4KIIIa D123 , males hemizygous for zw2 c21 or other zw2 alleles die as first instar larvae (Shannon et al., 1972).' should read 'Like PI4KIIIa D123 , males hemizygous for other zw2 alleles die as first instar larvae (Shannon et al., 1972).'The authors apologise to the readers for any confusion that this error might have caused. (2014) (PI4KIIIa) during oogenesis. We demonstrate that PI4KIIIa is required for production of plasma membrane PtdIns4P and PtdIns(4,5)P 2 and is crucial for actin organization, membrane trafficking and cell polarity. Female germ cells mutant for PI4KIIIa exhibit defects in cortical integrity associated with failure to recruit the cytoskeletal-membrane crosslinker Moesin and the exocyst subunit Sec5. These effects reflect a unique requirement for PI4KIIIa, as egg chambers from flies mutant for either of the other Drosophila PI4Ks, fwd or PI4KII, show Golgi but not plasma membrane phenotypes. Thus, PI4KIIIa is a vital regulator of a functionally distinct pool of PtdIns4P that is essential for PtdIns(4,5)P 2 -dependent processes in Drosophila development.

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Section: D123mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PI4KIIIα is required for cortical integrity and cell polarity during Drosophila oogenesis

Tan

Burgess

et al. 2014

Journal of Cell Science

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“…Furthermore, endocannabinoids have recently been identified as putative Smo inhibitors that are carried into the cell on liposomes and recruited by Ptc into endosomes, where they are thought to bind directly to Smo to inhibit its activity (Khaliullina et al, 2015). Ptc has also been implicated in regulating Smo activity by modulating phosphoinositiol levels in Drosophila; the loss of Ptc thus results in increased levels of PI4P, which in turn promotes Smo activation (Yavari et al, 2010).…”

Section: Hh Signal Transduction In Drosophilamentioning

confidence: 99%

Hedgehog signalling

2016

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The Hedgehog (Hh) signalling pathway is one of the key regulators of metazoan development. Hh proteins have been shown to play roles in many developmental processes and have become paradigms for classical morphogens. Dysfunction of the Hh pathway underlies a number of human developmental abnormalities and diseases, making it an important therapeutic target. Interest in Hh signalling thus extends across many fields, from evo-devo to cancer research and regenerative medicine. Here, and in the accompanying poster, we provide an outline of the current understanding of Hh signalling mechanisms, highlighting the similarities and differences between species.

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“…However, Smo localises to the plasma membrane in a Hh-independent manner when cellular phosphatidylinositol-4 phosphate (PI4P) levels are experimentally increased. Intriguingly, Ptc itself directly or indirectly downregulates PI4P accumulation (Yavari et al, 2010). This suggests an alternative order of events, whereby Ptc inactivation by Hh first drives Smo membrane localisation by modulating membrane phospholipids, with Smo phosphorylation and clustering occurring downstream.…”

Section: Introductionmentioning

confidence: 99%

“…These include lipidmodifying enzymes (Yavari et al, 2010), cAMP and protein kinase A (PKA) (Ogden et al, 2008), and the phosphatases PP1, PP4 and PP2A (Jia et al, 2009;Su et al, 2011). Regardless of the precise mechanism, Hh binding alleviates the inhibitory activity of Ptc towards Smo.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of the Smo tail is controlled by membrane localization and is dispensable for clustering

Kupinski

Raabe

Michel

et al. 2013

Journal of Cell Science

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SummaryThe Hedgehog (Hh) signalling cascade is highly conserved and involved in development and disease throughout evolution. Nevertheless, in comparison with other pathways, our mechanistic understanding of Hh signal transduction is remarkably incomplete. In the absence of ligand, the Hh receptor Patched (Ptc) represses the key signal transducer Smoothened (Smo) through an unknown mechanism. Hh binding to Ptc alleviates this repression, causing Smo redistribution to the plasma membrane, phosphorylation and opening of the Smo cytoplasmic tail, and Smo oligomerisation. However, the order and interdependence of these events is as yet poorly understood. We have mathematically modelled and simulated Smo activation for two alternative modes of pathway activation, with Ptc primarily affecting either Smo localisation or phosphorylation. Visualising Smo activation through a novel, fluorescence-based reporter allowed us to test these competing models. Here, we show that Smo localisation to the plasma membrane is sufficient for phosphorylation of the cytoplasmic tail in the presence of Ptc. Using fluorescence cross-correlation spectroscopy (FCCS), we also demonstrate that inactivation of Ptc by Hh induces Smo clustering irrespective of Smo phosphorylation. Our observations therefore support a model of Hh signal transduction whereby Smo subcellular localisation and not phosphorylation is the primary target of Ptc function.

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Role of Lipid Metabolism in Smoothened Derepression in Hedgehog Signaling

Cited by 94 publications

References 40 publications

PI4KIIIα is required for cortical integrity and cell polarity during Drosophila oogenesis

PI4KIIIα is required for cortical integrity and cell polarity during Drosophila oogenesis

Hedgehog signalling

Phosphorylation of the Smo tail is controlled by membrane localization and is dispensable for clustering

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