期刊
JOURNAL OF CELL SCIENCE
卷 128, 期 18, 页码 3456-3465出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.172775
关键词
Protein kinase B; Akt; Rapalogue dimerisation; Phosphoinositide; Subcellular compartment
类别
资金
- Ikerbasque Foundation of Science
- Spanish Ministry of Economy [BFU 2011-28566]
- Basque Government [IT838-13]
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)P-3] 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)P-3 has long been speculated upon. By using transfected and recombinant protein probes for PtdIns(3,4,5)P-3, we show that PtdIns(3,4,5)P-3 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)P-3-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.
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