Phosphoinositides Regulate Ciliary Protein Trafficking to Modulate Hedgehog Signaling
Open accessAbstract
Primary cilia interpret vertebrate Hedgehog (Hh) signals. Why cilia are essential for signaling is unclear. One possibility is that some forms of signaling require a distinct membrane lipid composition, found at cilia. We found that the ciliary membrane contains a particular phosphoinositide, PI(4)P, whereas a different phosphoinositide, PI(4,5)P2, is restricted to the membrane of the ciliary base. This distribution is created by Inpp5e, a ciliary phosphoinositide 5-phosphatase. Without Inpp5e, ciliary PI(4,5)P2 levels are elevated and Hh signaling is disrupted. Inpp5e limits the ciliary levels of inhibitors of Hh signaling, including Gpr161 and the PI(4,5)P2-binding protein Tulp3. Increasing ciliary PI(4,5)P2 levels or conferring the ability to bind PI(4)P on Tulp3 increases the ciliary localization of Tulp3. Lowering Tulp3 in cells lacking Inpp5e reduces ciliary Gpr161 levels and restores Hh signaling. Therefore, Inpp5e regulates ciliary membrane phosphoinositide composition, and Tulp3 reads out ciliary phosphoinositides to control ciliary protein localization, enabling Hh signaling.
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PKA activation in different subcellular regions is mediated by local cAMP production and anchoring of PKA to AKAPs.
“Activation of PKA in different subcellular regions is mediated by local cAMP production and anchoring of PKA to A-kinase anchoring proteins (AKAPs) 141.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [141]
The Results section on distinct ciliary compartments describes the localization of PI(4)P and PI(4,5)P2, not PKA activation. Searches of our full-text copy for PKA, cAMP, AKAP, and the proposed mechanism found no passage addressing local cAMP production or PKA anchoring. The copy provides neither support for nor a contradiction of the claim. (LLM, conf=0.76)
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References 54 · Cited by 330
- Authors
- Garcia-Gonzalo, F. R., Phua, S. C., Roberson, E. C., Garcia, G., Abedin, M., Schurmans, S., Inoue, T., & Reiter, J. F.
- Affiliations
- Johns Hopkins University (US)
- University of California, San Francisco (US)
- University of Liège (BE)
- Corresponding author
- Inoue, Takanari
- Reiter, Jeremy F.
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 34
- Issue
- 4
- Pages
- 400-409
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC4557815
- OpenAlex
- W1900540592
- Cited by
- 330
- References
- 54
- Citations by year
- 2026: 16 · 2025: 34 · 2024: 18 · 2023: 19 · 2022: 31 · 2021: 36 · 2020: 55 · 2019: 34 · 2018: 29 · 2017: 24 · 2016: 23 · 2015: 10
- FWCI
- 19.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Agency for Science, Technology and Research
- National Institutes of Health
- National Institute of General Medical Sciences (GM095941, R01GM095941)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK102910, R01DK102910, P30DK063720)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR054396, AR054396)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Keywords
- Hedgehog signaling, primary cilia, phosphoinositides, phosphatidylinositol 4,5-bisphosphate, INPP5E, phosphoinositide 5-phosphatase, TULP3, GPR161, ciliary protein trafficking, ciliary base
- MeSH terms
- Phosphoinositide 5-Phosphatases, Animals, Cilia, Cytoskeletal Proteins, Embryo, Mammalian, Fibroblasts, Models, Biological, Phosphatidylinositols, Phosphoric Monoester Hydrolases, Proteins, Signal Transduction, Phosphatidylinositol Phosphates, Phosphatidylinositol 4,5-Diphosphate, Protein Transport, Intercellular Signaling Peptides and Proteins, NIH 3T3 Cells, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Mice, Hedgehog Proteins
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