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Dev Cell. 2014 Mar 31;28(6):647-58. doi: 10.1016/j.devcel.2014.01.022.

PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function.

Author information

1
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
2
Laboratoire de Parasitologie Moléculaire, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, 6041 Charleroi, Belgium.
3
Leibniz Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
4
Centre for Diabetes, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
5
Laboratoire de Parasitologie Moléculaire, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, 6041 Charleroi, Belgium; Center for Microscopy and Molecular Imaging-CMMI, Université Libre de Bruxelles, 8 rue Adrienne Bolland, 6041 Gosselies, Belgium.
6
Division of Genetics and Cell Biology, Dibit San Raffaele Scientific Institute, 20132 Milan, Italy.
7
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. Electronic address: emilio.hirsch@unito.it.

Abstract

Multiple phosphatidylinositol (PtdIns) 3-kinases (PI3Ks) can produce PtdIns3P to control endocytic trafficking, but whether enzyme specialization occurs in defined subcellular locations is unclear. Here, we report that PI3K-C2α is enriched in the pericentriolar recycling endocytic compartment (PRE) at the base of the primary cilium, where it regulates production of a specific pool of PtdIns3P. Loss of PI3K-C2α-derived PtdIns3P leads to mislocalization of PRE markers such as TfR and Rab11, reduces Rab11 activation, and blocks accumulation of Rab8 at the primary cilium. These changes in turn cause defects in primary cilium elongation, Smo ciliary translocation, and Sonic Hedgehog (Shh) signaling and ultimately impair embryonic development. Selective reconstitution of PtdIns3P levels in cells lacking PI3K-C2α rescues Rab11 activation, primary cilium length, and Shh pathway induction. Thus, PI3K-C2α regulates the formation of a PtdIns3P pool at the PRE required for Rab11 and Shh pathway activation.

PMID:
24697898
PMCID:
PMC4042153
DOI:
10.1016/j.devcel.2014.01.022
[Indexed for MEDLINE]
Free PMC Article

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