AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.
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Abstract | Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations. |
Year of Publication | 2009
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Journal | Cancer Cell
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Volume | 16
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Issue | 1
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Pages | 21-32
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Date Published | 2009 Jul 07
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ISSN | 1878-3686
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URL | |
DOI | 10.1016/j.ccr.2009.04.012
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PubMed ID | 19573809
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PubMed Central ID | PMC2752826
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Links | |
Grant list | T32CA09172-33 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
R01 CA085912 / CA / NCI NIH HHS / United States
P01CA050661 / CA / NCI NIH HHS / United States
P30CA14051 / CA / NCI NIH HHS / United States
R33 CA128625 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
P50 CA098258 / CA / NCI NIH HHS / United States
U54 CA112967 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
R01CA085912 / CA / NCI NIH HHS / United States
R01 CA085912-09 / CA / NCI NIH HHS / United States
DP2 OD002750 / OD / NIH HHS / United States
P50CA112967 / CA / NCI NIH HHS / United States
P50CA093459 / CA / NCI NIH HHS / United States
R33CA128625 / CA / NCI NIH HHS / United States
DP2 OD002750-01 / OD / NIH HHS / United States
P01 CA050661 / CA / NCI NIH HHS / United States
P50 CA093459 / CA / NCI NIH HHS / United States
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