Abstract
Author SummaryThe ability of cells to survive in the absence of proliferation (cell division), differentiation (cell maturation) or activation allows tissues to maintain cell populations that are poised for rapid responses to damage, infections, or other physiological demands. While this “survival-only” response is fundamental to all physiological processes, the underlying mechanisms are not understood. Many growth factors are potent regulators of cell survival through their ability to bind specific cell surface receptors, which in turn activate specialized enzymes called kinases. Phosphoinositide 3-kinase (PI3K) is a dual specificity kinase that is known to be involved in cell survival and malignant transformation, and it is able to phosphorylate both lipid and protein substrates. While the PI3K lipid kinase activity has been extensively studied, the functional significance of its protein kinase activity remains unclear. Here we show that PI3K protein kinase activity can directly phosphorylate growth factor receptors on human hematopoietic (blood) cells to promote a “survival-only” response. We further show that the protein kinase activity of PI3K can be hijacked to result in uncontrolled growth factor receptor phosphorylation and the deregulated survival of leukemic cells. Our studies provide the first evidence that the protein kinase activity of PI3K can control cell survival and that this activity may be deregulated in cancer.
Highlights
A key mechanism by which growth factors and cytokines promote cell survival is via the phosphoinositide 3-kinase (PI3K) pathway and constitutive PI3K signaling is known to promote autonomous cell survival and transformation [1]
Consistent with our previous findings [10], Ser585 phosphorylation of the granulocyte macrophage colony stimulating factor (GM-CSF)/interleukin 3 (IL-3) bc receptor was constitutive in primary acute myeloid leukemia (AML) blasts (Figure 1C) and K562 chronic myeloid leukemia (CML) cells (Figure 1D) and was not affected by tyrosine kinase inhibitors (TKIs)
Little is known of the protein substrates of PI3K, our results suggested the possibility that the serine kinase activity of PI3K could phosphorylate Ser585
Summary
A key mechanism by which growth factors and cytokines promote cell survival is via the phosphoinositide 3-kinase (PI3K) pathway and constitutive PI3K signaling is known to promote autonomous cell survival and transformation [1]. The recruitment and activation of class 1A isoforms of PI3K (p110a, p110b, p110d) by cytokine and growth factor receptors leads to the phosphorylation of phosphatidyl inositol phosphates (PIPs) and the subsequent docking of pleckstrin homology (PH) domain proteins such as Akt that activate downstream signaling cascades and biological responses [1]. While much is known regarding the targets and biological functions of PI3K lipid signaling, little is known of the substrates and functional roles of its protein kinase activity. We and others have shown that the phosphorylation of specific serine residues in the cytoplasmic tails of growth factor and cytokine receptors is critical for initiating intracellular signaling pathways that selectively control cell survival [5,6,7,8,9]. Physiological picomolar (pM) concentrations of Author Summary
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