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Dissecting the cellular function of the rare signalling lipid PI(3,4)P2

Subject Area Cell Biology
Biochemistry
Term since 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 546311970
 
Phosphoinositides are membrane lipids that organize and regulate the activity of proteins at cellular membranes, thereby impinging on most aspects of cell physiology. Numerous proteins and cellular pathways are known to be regulated by the abundant phosphoinositides PI(3)P, PI(4)P and PI(4,5)P2, yet we have uncovered only a handful of effector proteins and few biological functions of the rare phosphoinositide PI(3,4)P2. Amongst these are the regulation of endocytosis and the turnover of cellular adhesions to the extracellular matrix at the plasma membrane. On lysosomes, in absence of growth factor signalling, PI(3,4)P2 mediates repression of the central metabolic signalling integrator mTORC1. However, we still lack a comprehensive understanding of the cellular roles of PI(3,4)P2, with major questions remaining regarding the effector proteins, the phosphatases and the regulatory networks both upstream and downstream of PI(3,4)P2. The overarching objectives of the proposed research therefore focus on three areas: (1) the identification of the effector proteome of PI(3,4)P2 at the plasma membrane and on lysosomes; (2) the identification and characterization of the phosphatases that turnover PI(3,4)P2 in these compartments, respectively; (3) an analysis of how cell state and levels of PI(3,4)P2 on lysosomes or the plasma membrane are linked, employing transcriptomic, proteomic and metabolomic approaches. We expect these studies to fill fundamental knowledge gaps of PI(3,4)P2 biology. Furthermore, this work pioneers technology for the application of single-cell omics approaches to the study of phosphoinositides, opening an unprecedented systems biological perspective on the regulatory networks that link phosphoinositide metabolism and cell state.
DFG Programme Research Grants
 
 

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