Figure 1. Potential Roles of p110β in Metabolism and Oncogenesis.

(A) Under conditions where PTEN is present, Akt is activated predominantly by the RTK-p110α pathway, as occurs in the liver after insulin stimulation. Insulin-induced activation of Akt results in the phosphorylation of FOXO transcription factors and ultimately, the inhibtion of target gene expression. However, p110β is required for full repression of glucoeneogenic gene expression (e.g., the PEPCK gene) by insulin, suggesting that this isoform activates downstream kinases in addition to Akt and/or regulates transcription factors in addition to FOXO. The specific activation of non-Akt kinases by p110β may require either the generation of spacially restricted pools of PIP₃ within the cell or the generation of quantities of PIP₃ exceeding those required for Akt activation.

(B) Under conditions where PTEN expression is reduced, as occurs in many human tumors, the basal level of PIP₃ is increased due to unopposed p110β activity. These increased basal levels of PIP₃ result in increased Akt activity and increased cell growth. In both scenarios (A and B) p110β may also function in a PIP₃-independent manner such that its catalytic activity is not required for regulation of downstream signaling. In this model, p110β serves as a “molecular scaffold” for recruiting additional catalytically active signaling molecules. See text for further details.