Oncogenic transformation induced by the p110β, -γ, and -δ isoforms of class I phosphoinositide 3-kinase

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Abstract
Class I phosphoinositide 3-kinase contains four isoforms of the catalytic subunit, p110α, -β, -γ, and -δ. At physiological levels of expression, the wild-type p110α isoform lacks oncogenic potential, but gain-of-function mutations and overexpression of p110α are correlated with oncogenicity. The p110β, -γ, and -δ isoforms induce transformation of cultured cells as wild-type proteins. This oncogenic potential requires kinase activity and can be suppressed by the target of rapamycin inhibitor rapamycin. The p110δ isoform constitutively activates the Akt signaling pathway; p110γ activates Akt only in the presence of serum. The isoforms differ in their requirements for upstream signaling. The transforming activity of the p110γ isoform depends on rat sarcoma viral oncogene homolog (Ras) binding; preliminary data suggest the same for p110β and indicate Ras-independent oncogenic potential of p110δ. The surprising oncogenic potential of the wild-type non-α isoforms of class I phosphoinositide 3-kinase may explain the dearth of cancer-specific mutations in these proteins, because these non-α isoforms could contribute to the oncogenic phenotype of the cell by differential expression.
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