ArticleDevelopment (Cambridge, England)2009
PP4 and PP2A regulate Hedgehog signaling by controlling Smo and Ci phosphorylation.
Article in Development (Cambridge, England), 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 84 citations in OpenAlex.
- Gene model for the ortholog ofmicroPublication biology · 2025Article
- Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response.Cell reports · 2024Article
- Phosphatidic acid binding to Patched contributes to the inhibition of Smoothened and Hedgehog signaling inScience signaling · 2023Article
- Dose-dependent phosphorylation and activation of Hh pathway transcription factors.Life science alliance · 2022Article
- Protein Phosphatase 4 Negatively Regulates the Immune Deficiency-NF-κB Pathway during theJournal of immunology (Baltimore, Md. : 1950) · 2021Article
- Review
- Targeting of SET/I2PP2A oncoprotein inhibits Gli1 transcription revealing a new modulator of Hedgehog signaling.Scientific reports · 2021Article
- Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of Suppressor of fused.Cell death & disease · 2020Article
- Phosphoproteomics of short-term hedgehog signaling in human medulloblastoma cells.Cell communication and signaling : CCS · 2020Article
- Functional roles of protein phosphatase 4 in multiple aspects of cellular physiology: a friend and a foe.BMB reports · 2020Review
- The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors.Developmental neuroscience · 2020Article
- Phosphorylation of Ci/Gli by Fused Family Kinases Promotes Hedgehog Signaling.Developmental cell · 2019Article
- Proteostasis in the Hedgehog signaling pathway.Seminars in cell & developmental biology · 2019Review
- Blood-Bile Barrier: Morphology, Regulation, and Pathophysiology.Gene expression · 2019Review
- Article
- A cell based, high throughput assay for quantitative analysis of Hedgehog pathway activation using a Smoothened activation sensor.Scientific reports · 2017Article
- Screening and identification of host proteins interacting with Theileria annulata cysteine proteinase (TaCP) by yeast-two-hybrid system.Parasites & vectors · 2017Article
- The emerging roles of phosphatases in Hedgehog pathway.Cell communication and signaling : CCS · 2017Review
- The protein phosphatase 4 complex promotes the Notch pathway andBiology open · 2017Article
- SUMO regulates the activity of Smoothened and Costal-2 in Drosophila Hedgehog signaling.Scientific reports · 2017Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The seven-transmembrane protein Smoothened (Smo) and Zn-finger transcription factor Ci/Gli are crucial components in Hedgehog (Hh) signal transduction that mediates a variety of processes in animal development. In Drosophila, multiple kinases have been identified to regulate Hh signaling by phosphorylating Smo and Ci; however, the phosphatase(s) involved remain obscured. Using an in vivo RNAi screen, we identified PP4 and PP2A as phosphatases that influence Hh signaling by regulating Smo and Ci, respectively. RNAi knockdown of PP4, but not of PP2A, elevates Smo phosphorylation and accumulation, leading to increased Hh signaling activity. Deletion of a PP4-interaction domain (amino acids 626-678) in Smo promotes Smo phosphorylation and signaling activity. We further find that PP4 regulates the Hh-induced Smo cell-surface accumulation. Mechanistically, we show that Hh downregulates Smo-PP4 interaction that is mediated by Cos2. We also provide evidence that PP2A is a Ci phosphatase. Inactivating PP2A regulatory subunit (Wdb) by RNAi or by loss-of-function mutation downregulates, whereas overexpressing regulatory subunit upregulates, the level and thus signaling activity of full-length Ci. Furthermore, we find that Wdb counteracts kinases to prevent Ci phosphorylation. Finally, we have obtained evidence that Wdb attenuates Ci processing probably by dephosphorylating Ci. Taken together, our results suggest that PP4 and PP2A are two phosphatases that act at different positions of the Hh signaling cascade.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.