Editors' ChoiceCancer

Oncogenic Activities of PI3K Isoforms

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Science's STKE  07 Feb 2006:
Vol. 2006, Issue 321, pp. tw52
DOI: 10.1126/stke.3212006tw52

Although each of the four isoforms--p110α, p110β, p110δ, and p110γ--of the catalytic subunit of phosphoinositide 3-kinase (PI3K) has been implicated in cancer, the gene encoding p110α is the only one for which oncogenic mutations have been reported. Kang et al. explored the transformation ability of the p110 isoforms and found that forced expression of the human β, γ, or δ isoforms in chicken embryo fibroblasts induced the cellular transformation. Addition of a myristoylation signal to the proteins greatly enhanced the transformation efficiency of the β isoform and had a lesser effect on the γ or δ isoforms, which were already potent transforming agents. Transformation required the lipid kinase activity of the enzymes, but not the protein kinase activity, based on analysis of the transformation ability of mutant forms of the enzymes. The p110δ isoform stimulated the Akt pathway (measured as phosphorylation of Akt and p70 S6 kinase) even in the absence of serum, whereas serum was required for activation of Akt in cells expressing the β or γ isoforms. Mutations that disrupt the interaction with Ras, which connects p110 activity to growth factor stimulation, inhibited the transformation ability of the β and γ isoforms but did not inhibit the oncogenic potential of p110δ. Common to the oncogenicity of all isoforms was the activation of the Akt to TOR (target of rapamycin) pathway, because rapamycin, which inhibits TOR activity, blocked transformation. Thus, differences in the β, γ, and δ isoforms' oncogenicity may derive from differences in upstream activation, such as misexpression in an inappropriate cell, or at an inappropriate time, or overexpression, because these isoforms possess transformation potential in the absence of activating mutations.

S. Kang, A. Denley, B. Vanhaesebroeck, P. K. Vogt, Oncogenic transformation induced by the p110β, -γ, and -δ isoforms of class I phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. U.S.A. 103, 1289-1294 (2006). [Abstract] [Full Text]

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