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Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
Published on: January 31, 2025
PP4 and PP2A regulate Hedgehog signaling by controlling Smo and Ci phosphorylation
Hongge Jia1, Yajuan Liu, Wei Yan
1Sealy Center for Cancer Cell Biology, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Development (Cambridge, England)
|December 18, 2008
Summary
Two phosphatases, PP4 and PP2A, regulate Hedgehog (Hh) signaling by targeting Smoothened (Smo) and Ci/Gli, respectively. PP4 influences Smo phosphorylation and cell-surface accumulation, while PP2A dephosphorylates Ci, impacting Hh pathway activity.
Area of Science:
- Developmental Biology
- Molecular Cell Biology
- Signal Transduction
Background:
- Hedgehog (Hh) signaling is vital for animal development, involving Smoothened (Smo) and Ci/Gli.
- Kinases regulate Hh signaling by phosphorylating Smo and Ci.
- The phosphatases involved in Hh signaling remain largely unknown.
Purpose of the Study:
- To identify phosphatases regulating Hh signal transduction in Drosophila.
- To elucidate the roles of PP4 and PP2A in Smo and Ci/Gli regulation.
- To understand the mechanisms by which these phosphatases influence Hh pathway activity.
Main Methods:
- In vivo RNA interference (RNAi) screen to identify phosphatases.
- Analysis of Smoothened (Smo) phosphorylation, accumulation, and cell-surface localization.
- Investigation of Ci/Gli dephosphorylation and processing.
- Assessment of Hh signaling activity.
Main Results:
- PP4 and PP2A were identified as key phosphatases in Hh signaling.
- PP4 knockdown increased Smo phosphorylation and signaling, affecting Smo cell-surface accumulation.
- PP4 interaction with Smo was modulated by Cos2, and Hh signaling downregulated this interaction.
- PP2A was identified as a Ci phosphatase, with its regulatory subunit (Wdb) controlling Ci levels and activity.
- Wdb counteracted kinases and attenuated Ci processing, likely via dephosphorylation.
Conclusions:
- PP4 and PP2A act as critical phosphatases in the Hh signaling cascade.
- PP4 regulates Smo protein levels and localization, influencing pathway activation.
- PP2A, through its regulatory subunit Wdb, controls Ci/Gli phosphorylation and processing.
- These findings reveal distinct roles for PP4 and PP2A at different levels of Hh signal transduction.
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