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Oncogenic activity of the regulatory subunit p85? of phosphatidylinositol 3-kinase (PI3K).

ABSTRACT: Expression of the regulatory subunit p85? of PI3K induces oncogenic transformation of primary avian fibroblasts. The transformed cells proliferate at an increased rate compared with nontransformed controls and show elevated levels of PI3K signaling. The oncogenic activity of p85? requires an active PI3K-TOR signaling cascade and is mediated by the p110? and p110? isoforms of the PI3K catalytic subunit. The data suggest that p85? is a less effective inhibitor of the PI3K catalytic subunit than p85? and that this reduced level of p110 inhibition accounts for the oncogenic activity of p85?.

SUBMITTER: Ito Y

PROVIDER: S-EPMC4250105 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Oncogenic activity of the regulatory subunit p85β of phosphatidylinositol 3-kinase (PI3K).

Ito Yoshihiro Y Hart Jonathan R JR Ueno Lynn L Vogt Peter K PK

Proceedings of the National Academy of Sciences of the United States of America 20141110 47

Expression of the regulatory subunit p85β of PI3K induces oncogenic transformation of primary avian fibroblasts. The transformed cells proliferate at an increased rate compared with nontransformed controls and show elevated levels of PI3K signaling. The oncogenic activity of p85β requires an active PI3K-TOR signaling cascade and is mediated by the p110α and p110β isoforms of the PI3K catalytic subunit. The data suggest that p85β is a less effective inhibitor of the PI3K catalytic subunit than p8 ...[more]

PMID: 25385636

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Domain analysis reveals striking functional differences between the regulatory subunits of phosphatidylinositol 3-kinase (PI3K), p85α and p85β.

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The regulatory subunits of PI3K, p85α and p85β, differentially affect BRD7-mediated regulation of insulin signaling.

Project description:Bromodomain-containing protein 7 (BRD7) has been shown to interact with the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), p85, in the insulin signaling pathway. Here, we show that upregulation of hepatic BRD7 improves glucose homeostasis even in the absence of either p85 isoform, p85α or p85β. However, BRD7 leads to differential activation of downstream effector proteins in the insulin signaling pathway depending on which isoform of p85 is present. In the presence of only p85α, BRD7 overexpression increases phosphorylation of insulin receptor (IR) upon insulin stimulation, without increasing the recruitment of p85 to IR substrate. Overexpression of BRD7 also increases activation of Akt in response to insulin, but does not affect basal phosphorylation levels of Akt. Meanwhile, the phosphorylation of glycogen synthase kinase 3β (GSK3β) is increased by overexpression of BRD7. On the other hand, in the presence of only p85β, BRD7 overexpression does not affect phosphorylation levels of IR, and Akt phosphorylation is not affected by insulin stimulation following BRD7 upregulation. However, BRD7 overexpression leads to increased basal phosphorylation levels of Akt and GSK3β. These data demonstrate that BRD7's action on glucose homeostasis does not require the presence of both p85 isoforms, and p85α and p85β have unique roles in insulin signaling in the liver.

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