2. Academic Validation
  3. A class I PI3K signalling network regulates primary cilia disassembly in normal physiology and disease

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

  • Nat Commun. 2024 Aug 21;15(1):7181. doi: 10.1038/s41467-024-51354-1.
Sarah E Conduit 1,  Wayne Pearce 2,  Amandeep Bhamra 3,  Benoit Bilanges 2,  Laura Bozal-Basterra 4 5,  Lazaros C Foukas 6,  Mathias Cobbaut 7,  Sandra D Castillo 8,  Mohammad Amin Danesh 2,  Mahreen Adil 2,  Arkaitz Carracedo 4 5 9 10 11,  Mariona Graupera 5 8 12,  Neil Q McDonald 7 13,  Peter J Parker 14 15,  Pedro R Cutillas 16,  Silvia Surinova 3,  Bart Vanhaesebroeck 17
Affiliations

Affiliations

  • 1 Cell Signalling, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK. s.conduit@ucl.ac.uk.
  • 2 Cell Signalling, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
  • 3 Proteomics Research Translational Technology Platform, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
  • 4 Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160, Derio, Spain.
  • 5 Centro de Investigación Biomédica En Red de Cáncer (CIBERONC), 28029, Madrid, Spain.
  • 6 Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, WC1E 6BT, UK.
  • 7 Signalling and Structural Biology laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • 8 Endothelial Pathobiology and Microenvironment, Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
  • 9 Translational Prostate Cancer Research Laboratory, CIC bioGUNE-Basurto, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.
  • 10 IKERBASQUE, Basque Foundation for Science, 48009, Bilbao, Spain.
  • 11 Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), P.O. Box 644, E-48080, Bilbao, Spain.
  • 12 ICREA, Institució Catalana de Recerca i Estudis Avançats, Pg. Lluís Companys 23, Barcelona, Spain.
  • 13 Institute of Structural and Molecular Biology, School of Natural Sciences, Birkbeck College, Malet Street, London, WC1E 7HX, UK.
  • 14 The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • 15 King's College London, Guy's Campus, London, UK.
  • 16 Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
  • 17 Cell Signalling, UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK. bart.vanh@ucl.ac.uk.
PMID: 39168978 DOI: 10.1038/s41467-024-51354-1
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.

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