Abstract
Full activation of protein kinase B (PKB/Akt) requires phosphorylation on Thr-308 and Ser-473. It is well established that Thr-308 is phosphorylated by 3-phosphoinositide-dependent kinase-1 (PDK1). Ser-473 phosphorylation is mediated by both mammalian target of rapamycin-rictor complex (mTORC2) and DNA-dependent protein kinase (DNA-PK) depending on type of stimulus. However, the physiological role of DNA-PK in the regulation of PKB phosphorylation remains to be established. To address this, we analyzed basal, insulin-induced, and DNA damage-induced PKB Ser-473 phosphorylation in DNA-PK catalytic subunit-null DNA-PKcs(-/-) mice. Our results revealed that DNA-PK is required for DNA damage-induced phosphorylation but dispensable for insulin- and growth factor-induced PKB Ser-473 phosphorylation. Moreover, DNA-PKcs(-/-) mice showed a tissue-specific increase in basal PKB phosphorylation. In particular, persistent PKB hyperactivity in the thymus apparently contributed to spontaneous lymphomagenesis in DNA-PKcs(-/-) mice. Significantly, these tumors could be prevented by deletion of PKBalpha. These findings reveal stimulus-specific regulation of PKB activation by specific upstream kinases and provide genetic evidence of PKB deregulation in DNA-PKcs(-/-) mice.
Highlights
Activation of protein kinase B (PKB) requires phosphorylation at two key regulatory sites as follows: Thr-308 and Ser-473
We investigated the role of DNA-PK in basal, insulin-induced, and DNA damage-induced phosphorylation of PKB Ser-473 under physiological conditions
We report that DNA-PK phosphorylated PKB on Ser-473 upon DNA damage induced by ␥-irradiation in vivo
Summary
Activation of PKB requires phosphorylation at two key regulatory sites as follows: Thr-308 and Ser-473 (of PKB␣). Analysis of basal PKB Ser-473 phosphorylation in DNA-PKcsϪ/Ϫ mice showed tissue-specific deregulation of the PKB/FoxO pathway. This implies stimulus-specific regulation of PKB activation by PKB Is Hyperactivated in DNAPKcsϪ/Ϫ Thymus—To investigate how loss of DNA-PK is reflected in basal PKB Ser-473 phosphorylation, we analyzed a panel of tissues from wild-type and DNA-PKcsϪ/Ϫ mice.
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