Model for the regulation of cell survival by the protein kinase or lipid kinase activities of PI3K.

<p>Left panel: Low physiological concentrations of cytokine in the picomolar range activate the protein kinase activity of PI3K leading to Ser608 phosphorylation of p85 and Ser585 phosphorylation of the GM-CSF/IL-3 βc receptor (red circles) to promote cell survival in the absence of phosphotyrosine pathways and proliferation (survival-only response). Middle panel: Nanomolar concentrations of cytokine result in activation of the JAK2 tyrosine kinase, Tyr577 phosphorylation of βc, the recruitment of a Shc:grb2:GAB2:PI3K signaling complex to Tyr577 (red circle) <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001515#pbio.1001515-Guthridge2" target="_blank">[6]</a>,<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001515#pbio.1001515-Gu1" target="_blank">[33]</a>, and the activation of canonical PI3K lipid signaling via Akt to promote cell proliferation and survival. Right panel: Blockade of the p110α catalytic subunit of PI3K inhibits both protein kinase targets (Ser585) and lipid kinase targets (Akt) and induces apoptosis in primary human AML cells.