Research ArticleCell Biology

Proliferative and Antiapoptotic Signaling Stimulated by Nuclear-Localized PDK1 Results in Oncogenesis

Sci. Signal.  06 Nov 2012:
Vol. 5, Issue 249, pp. ra80
DOI: 10.1126/scisignal.2003065

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PDK1 Goes Nuclear

Many tumors exhibit enhanced phosphoinositide 3-kinase (PI3K) signaling, which results in increased activity of the kinase Akt and cellular proliferation. Phosphoinositide-dependent protein kinase 1 (PDK1) activates Akt at the plasma membrane downstream of PI3K; however, in cells in which PI3K signaling is enhanced, some PDK1 is localized to the nucleus. Kikani et al. showed that nuclear localization of PDK1 in mouse embryonic fibroblasts (MEFs) both enhanced Akt-dependent proliferation and inhibited proapoptotic signaling. Transfer of MEFs expressing a nuclear-localized mutant PDK1, but not wild-type PDK1, into athymic nude mice resulted in the robust formation of solid tumors. Analysis of human prostate tumor samples revealed that greater nuclear localization of PDK1 correlated with higher-grade tumors. Together, these data suggest that PDK1 in the nucleus is oncogenic and that therapeutic blocking of the nuclear translocation of PDK1 may be effective in treating cancers with enhanced PI3K activity.