Classically, the main and only well-characterized function of PI3K is PI(3,4,5)P3 production through the phosphorylation of PI(4,5)P2, in response to the activation of transmembrane receptors at the cell surface. PI(3,4,5)P3 then acts as a second messenger which activates a variety of downstream effectors. Using bioinformatics and chemically-inducible dimerization approaches, we found that PI3K senses and induces membrane deformation, independently from production of PI(3,4,5)P3. Further characterization implicates importance of these functions in cell migration and receptor-mediated endocytosis.
The Inoue Lab Research Overview:
Complexity in signaling networks is often derived from co-opting one set of molecules for multiple operations. Understanding how cells achieve such sophisticated processing using a finite set of molecules within a confined space –what we call the “signaling paradox”- is critical to biology and engineering as well as the emerging field of synthetic biology. We have recently developed a series of chemical-molecular tools that allow for inducible, quick-onset and specific perturbation of various signaling molecules. Using this novel technique in conjunction with fluorescence imaging, microfabricated devices, quantitative analysis and computational modeling, we are dissecting intricate signaling networks. In particular, we investigate positive-feedback mechanisms underlying the initiation of neutrophil chemotaxis (known as symmetry breaking), as well as spatio-temporally compartmentalized signaling of Ras and membrane lipids such as phosphoinositides. In parallel, we also try to understand how cell morphology affects biochemical pathways inside cells. Ultimately, we will generate completely orthogonal machinery in cells to achieve existing, as well as novel, cellular functions. Our synthetic, multidisciplinary approach will elucidate the signaling paradox created by nature.