A class I PI3K signalling network regulates primary cilia disassembly in normal physiology and disease

Sarah E. Conduit (), Wayne Pearce, Amandeep Bhamra, Benoit Bilanges, Laura Bozal-Basterra, Lazaros C. Foukas, Mathias Cobbaut, Sandra D. Castillo, Mohammad Amin Danesh, Mahreen Adil, Arkaitz Carracedo, Mariona Graupera, Neil Q. McDonald, Peter J. Parker, Pedro R. Cutillas, Silvia Surinova and Bart Vanhaesebroeck ()
Additional contact information
Sarah E. Conduit: University College London
Wayne Pearce: University College London
Amandeep Bhamra: University College London
Benoit Bilanges: University College London
Laura Bozal-Basterra: Building 801A
Lazaros C. Foukas: University College London
Mathias Cobbaut: 1 Midland Road
Sandra D. Castillo: Josep Carreras Leukaemia Research Institute
Mohammad Amin Danesh: University College London
Mahreen Adil: University College London
Arkaitz Carracedo: Building 801A
Mariona Graupera: Centro de Investigación Biomédica En Red de Cáncer (CIBERONC)
Neil Q. McDonald: 1 Midland Road
Peter J. Parker: The Francis Crick Institute
Pedro R. Cutillas: Queen Mary University of London
Silvia Surinova: University College London
Bart Vanhaesebroeck: University College London

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract 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 PIP3 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.

Date: 2024
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DOI: 10.1038/s41467-024-51354-1

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