A Study on an Intracellular Signaling Molecule, Phosphinositide 3-Kinase

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The mechanism by which stimulation of GTP-binding protein-coupled receptors activates cellular phosphoinositide 3-kinase (PI 3-kinase) was examined. It is known that stimulation of insulin or growth factor receptors activates PI 3-kinase by producing tyrosine-phosphorylated peptide that associates with and stimulates the p85/p110 subtype of the enzyme. However, such a tyrosine-phosphorylated protein can not be found in the neutrophils stimulated by fMLP,in spite that a marked accumulation of PIP_3, a product of PI 3-kinase, can be observed in the cells. At the beginning of this study, we found the occurrence of PI 3 -kinase activity that is unaffected by tyrosine-phosphorylated proteins but is stimulated by betagamma subunits of GTP-binding proteins (Gbetagamma). Similar results were obtained by other groups and more recently one subtype of Gbetagamma-sensitive PI 3-kinase (p110gamma) was cloned. These studies seemed to indicate that GTP-binding proteins and tyrosine kinases act independently and stimulate the different subtypes of PI 3-kinase. We found later, however, that co-stimulation of cells with insulin and fMLP causes synergistic accumulation of PIP_3. We also found in cell-free systems the occurrence of PI 3-kinase that can be synergistically activated by tyrosine-phosphorylated peptide and Gbetagamma. We are now examining for a physiological role of this novel type of regulation.