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

Class I phosphoinositide 3-kinase contains four isoforms of the catalytic subunit, p110 alpha, -beta, -gamma, and -delta. At physiological levels of expression, the wild-type p110 alpha isoform lacks oncogenic potential, but gain-of-function mutations and overexpression of p110a are correlated with oncogenicity. The p110 beta, -gamma, and -delta 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 p110 delta isoform constitutively activates the Akt signaling pathway; p110 gamma activates Akt only in the presence of serum. The isoforms differ in their requirements for upstream signaling. The transforming activity of the p110 gamma isoform depends on rat sarcoma viral oncogene homolog (Ras) binding; preliminary data suggest the same for p110 beta and indicate Ras-independent oncogenic potential of p110 delta. The surprising oncogenic potential of the wild-type non-a isoforms of class I phosphoinositide 3-kinase may explain the dearth of cancer-specific mutations in these proteins, because these non-a isoforms could contribute to the oncogenic phenotype of the cell by differential expression.