A class I PI3K signalling network regulates primary cilia disassembly in normal physiology and disease
Primary cilia are antenna-like organelles which sense extracellular cues and act as signalling hubs. Cilia dysfunction causes a heterogeneous group of disorders known as ciliopathy syndromes affecting most organs. Cilia disassembly, the process by which cells lose their cilium, is poorly understood but frequently observed in disease and upon cell transformation. Here, we uncover a role for the PI3Kα signalling enzyme in cilia disassembly. Genetic PI3Kα-hyperactivation, as observed in PIK3CA-related overgrowth spectrum (PROS) and cancer, induced a ciliopathy-like phenotype during mouse development. Mechanistically, PI3Kα and PI3Kβ produce the PIP<sub>3</sub> lipid at the cilia transition zone upon disassembly stimulation. PI3Kα activation initiates cilia disassembly through a kinase signalling axis via the PDK1/PKCι kinases, the CEP170 centrosomal protein and the KIF2A microtubule-depolymerising kinesin. Our data suggest diseases caused by PI3Kα-activation may be considered 'Disorders with Ciliary Contributions', a recently-defined subset of ciliopathies in which some, but not all, of the clinical manifestations result from cilia dysfunction.
Authors
- Mathias Cobbaut (ORCID: https://orcid.org/0000-0003-0279-0336)
- Sandra D. Castillo (ORCID: https://orcid.org/0000-0002-7007-3155)
- Benoît Bilanges (ORCID: https://orcid.org/0000-0003-4400-3716)
- Arkaitz Carracedo (ORCID: https://orcid.org/0000-0001-5957-1260)
- Neil Q. McDonald (ORCID: https://orcid.org/0000-0003-0975-6325)
- Mariona Graupera (ORCID: https://orcid.org/0000-0003-4608-4185)
- Silvia Šurinová (ORCID: https://orcid.org/0000-0003-0442-9595)
- Amandeep Bhamra (ORCID: https://orcid.org/0000-0002-7464-6387)
- Laura Bozal‐Basterra (ORCID: https://orcid.org/0000-0002-4858-2199)
- Mahreen Adil (ORCID: https://orcid.org/0000-0002-9222-5041)
- Pedro R. Cutillas (ORCID: https://orcid.org/0000-0002-3426-2274)
- Bart Vanhaesebroeck (ORCID: https://orcid.org/0000-0002-7074-3673)
- Sarah E. Conduit (ORCID: https://orcid.org/0000-0002-5075-8851)
- Lazaros C. Foukas (ORCID: https://orcid.org/0000-0002-6551-8789)
- Wayne Pearce (ORCID: https://orcid.org/0000-0001-5407-4767)
- Peter J. Parker (ORCID: https://orcid.org/0000-0001-5907-6980)
- Mohammad Amin Danesh (ORCID: https://orcid.org/0009-0002-8580-6793)
Institutions
- Ikerbasque (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Queen Mary University of London (GB)
- University of the Basque Country (ES)
- King's College London (GB)
- The Francis Crick Institute (GB)
- Cancer Research UK (GB)
- BioCruces Health research Institute (ES)
- Josep Carreras Leukaemia Research Institute (ES)
- CIC bioGUNE (ES)
- CRUK Lung Cancer Centre of Excellence (GB)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- University College London (GB)
- Birkbeck, University of London (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1038/s41467-024-51354-1
- Citations
- 11
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 6.05
Funders
- Wellcome Trust
- Francis Crick Institute
- PTEN Research
- Cancer Research UK
- National Institute for Health and Care Research
- University College London
- European Commission
- Centro de Investigación Biomédica en Red de Cáncer
- Horizon 2020 Framework Programme
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación