Document Detail

Akt/PKB localisation and 3' phosphoinositide generation at sites of epithelial cell-matrix and cell-cell interaction.
MedLine Citation:
PMID:  10226029     Owner:  NLM     Status:  MEDLINE    
Protein kinase B (PKB or Akt) is a mitogen-regulated protein kinase involved in the protection of cells from apoptosis, the promotion of cell proliferation and diverse metabolic responses [1]. Its activation is initiated by the binding of 3' phosphorylated phosphoinositide lipids to its pleckstrin homology (PH) domain, resulting in the induction of activating phosphorylation at residues Thr308 and Ser473 by upstream kinases such as phosphoinositide-dependent protein kinase-1 (PDK1) [2]. Adhesion of epithelial cells to extracellular matrix leads to protection from apoptosis via the activation of phosphoinositide (PI) 3-kinase and Akt/PKB through an unknown mechanism [3] [4]. Here, we use the localisation of Akt/PKB within the cell to probe the sites of induction of PI 3-kinase activity. In fibroblasts, immunofluorescence microscopy showed that endogenous Akt/PKB localised to membrane ruffles at the outer edge of the cell following mitogen treatment as did green fluorescent protein (GFP) fusions with full-length Akt/PKB or its PH domain alone. In epithelial cells, the PH domain of Akt/PKB localised to sites of cell-cell and cell-matrix contact, distinct from focal contacts, even in the absence of serum. As this localisation was disrupted by PI 3-kinase inhibitory drugs and by mutations that inhibit interaction with phosphoinositides, it is likely to represent the sites of constitutive 3' phosphoinositide generation that provide a cellular survival signal. We propose that the attachment-induced, PI-3-kinase-mediated survival signal in epithelial cells is generated not only by cell-matrix interaction but also by cell-cell interaction.
S J Watton; J Downward
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Current biology : CB     Volume:  9     ISSN:  0960-9822     ISO Abbreviation:  Curr. Biol.     Publication Date:  1999 Apr 
Date Detail:
Created Date:  1999-06-01     Completed Date:  1999-06-01     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9107782     Medline TA:  Curr Biol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  433-6     Citation Subset:  IM    
Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / antagonists & inhibitors
3T3 Cells / cytology,  drug effects,  metabolism
Binding Sites
Blood Proteins / genetics
Cell Communication
Cell Line
Chromones / pharmacology
Enzyme Inhibitors / pharmacology
Epidermal Growth Factor / pharmacology
Epithelial Cells / cytology,  drug effects,  metabolism*
Extracellular Matrix / metabolism
Fetal Blood / chemistry
Fluorescent Antibody Technique
Green Fluorescent Proteins
Insulin / pharmacology
Luminescent Proteins / genetics
Morpholines / pharmacology
Phosphatidylinositols / biosynthesis*,  chemistry
Platelet-Derived Growth Factor / pharmacology
Protein-Serine-Threonine Kinases*
Proto-Oncogene Proteins / analysis*,  genetics
Proto-Oncogene Proteins c-akt
Recombinant Fusion Proteins / analysis,  genetics
Sphingosine / analogs & derivatives,  pharmacology
Reg. No./Substance:
0/Blood Proteins; 0/Chromones; 0/Enzyme Inhibitors; 0/Luminescent Proteins; 0/Morpholines; 0/N-acetylsphingosine; 0/Phosphatidylinositols; 0/Phosphoproteins; 0/Platelet-Derived Growth Factor; 0/Proto-Oncogene Proteins; 0/Recombinant Fusion Proteins; 0/platelet protein P47; 11061-68-0/Insulin; 123-78-4/Sphingosine; 147336-22-9/Green Fluorescent Proteins; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 62229-50-9/Epidermal Growth Factor; EC 3-Kinase; EC Kinases; EC Proteins c-akt

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