title: Endomembrane PtdIns(3,4,5)P3 activates the PI3K-Akt pathway.
abstract: PKB/Akt activation is a common step in tumour growth, proliferation and survival. Akt activation is understood to occur at the plasma membrane of cells in response to growth factor stimulation and local production of the phosphoinositide lipid phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] following phosphoinositide 3-kinase (PI3K) activation. The metabolism and turnover of phosphoinositides is complex--they act as signalling molecules as well as structural components of biological membranes. The localisation and significance of internal pools of PtdIns(3,4,5)P3 has long been speculated upon. By using transfected and recombinant protein probes for PtdIns(3,4,5)P3, we show that PtdIns(3,4,5)P3 is enriched in the nuclear envelope and early endosomes. By exploiting an inducible dimerisation device to recruit Akt to these compartments, we demonstrate that Akt can be locally activated in a PtdIns(3,4,5)P3-dependent manner and has the potential to phosphorylate compartmentally localised downstream substrates. This could be an important mechanism to regulate Akt isoform substrate specificity or influence the timing and duration of PI3K pathway signalling. Defects in phosphoinositide metabolism and localisation are known to contribute to cancer, suggesting that interactions at subcellular compartments might be worthwhile targets for therapeutic intervention.
authors.affiliation: Cell Biophysics Laboratory, Cancer Research UK, London WC2A 3LY, UK.
authors.forename: Nirmal
authors.initials: N
authors.lastname: Jethwa
authors.affiliation: Cell Biophysics Laboratory, Cancer Research UK, London WC2A 3LY, UK.
authors.forename: Gary H C
authors.initials: GH
authors.lastname: Chung
authors.affiliation: Cell Biophysics Laboratory, Cancer Research UK, London WC2A 3LY, UK Unidad de Biofísica (CSIC, UPV/EHU), Universidad del País Vasco, Barrio Sarriena s/n, Leioa 48940, Spain Cell Biophysics Laboratory, Ikerbasque Basque Foundation for Science, Unidad de Biofísica (CSIC, UPV/EHU) and Research Centre for Experimental Marine Biology and Biotechnology (PiE), University of the Basque Country (UPV/EHU), Leioa 48940, Spain.
authors.forename: Marta G
authors.initials: MG
authors.lastname: Lete
authors.affiliation: Unidad de Biofísica (CSIC, UPV/EHU), Universidad del País Vasco, Barrio Sarriena s/n, Leioa 48940, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Alonso
authors.affiliation: Cell Biophysics Laboratory, Cancer Research UK, London WC2A 3LY, UK Signalling Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Byrne
authors.affiliation: Cell Biophysics Laboratory, Cancer Research UK, London WC2A 3LY, UK Protein Phosphorylation Laboratory, The Francis Crick Institute, London WC2A 3LY, UK.
authors.forename: Véronique
authors.initials: V
authors.lastname: Calleja
authors.affiliation: Cell Biophysics Laboratory, Cancer Research UK, London WC2A 3LY, UK Cell Biophysics Laboratory, Ikerbasque Basque Foundation for Science, Unidad de Biofísica (CSIC, UPV/EHU) and Research Centre for Experimental Marine Biology and Biotechnology (PiE), University of the Basque Country (UPV/EHU), Leioa 48940, Spain banafshe.larijani@ikerbasque.org.
authors.forename: Banafshé
authors.initials: B
authors.lastname: Larijani
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity; D014162:Transfection
chemical_list: D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Phosphoinositide; Protein kinase B; Rapalogue dimerisation; Subcellular compartment