The dual specificity
protein/
lipid kinase, phosphoinositide 3-kinase (PI3K), promotes
growth factor-mediated cell survival and is frequently deregulated in
cancer. However, in contrast to canonical
lipid-
kinase functions, the role of PI3K
protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile
protein kinases from primary human
acute myeloid leukemia (AML) cells that phosphorylate
serine residues in the cytoplasmic portion of
cytokine receptors to promote hemopoietic cell survival. We have isolated a
kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the
interleukin 3 (IL-3) and
granulocyte macrophage colony stimulating factor (
GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of
cytokine in the picomolar range were sufficient for activating the
protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K
lipid kinase signaling or promote proliferation. Blockade of PI3K
lipid signaling by expression of the
pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of
cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in
lipid kinase activity but retains
protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of
cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in
cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the
protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the
GM-CSF and
IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in
cancer.