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Elucidating cell-shape-dependent cellular signaling
The cell membrane is an essential component of cells that distinguishes the inside and outside of the cell. Each type of cell has a specific shape that is determined by the plasma membrane. The membrane receives every stimulus to cells, but how it behaves is not well understood. The shape of the plasma membrane is determined by the support of the actin cytoskeleton, of which regulation by WASP, N-WASP, WAVE1, and WAVE2 proteins has been extensively studied. Our lab will focus on the mechanisms connecting the membrane to the cytoskeleton (one of the seminal reviews in Nature Reviews). Our lab also focuses on membrane-binding proteins that connect the membrane to intracellular signaling for a variety of cellular functions, including proliferation and morphological changes. The roles of lipid composition of the membrane, including the saturation or unsaturation of fatty acids, are examined using the membrane-binding proteins. These complex cellular processes will also be analyzed using images of molecule localization.
Elucidating cell-shape-dependent intra- and inter-cellular signaling
~ Filopodia and Extracellular Vesicles (EVs) ~
The intracellular signaling cascade became understood by observing molecule-molecule interactions. However, the spatial organization of these signaling cascades had not been studied so well. We established the BAR domain superfamily proteins that remodel membrane shape into various curvatures through the discovery of membrane deformation by the I-BAR/IMD domain and the F-BAR/EFC domain, and then dictate the intracellular signaling cascades through liquid-liquid phase separation (LLPS).
The parts of the cells are released and delivered to the neighboring cells. These extracellular vesicles (exosomes and ectosomes; our opinion in Nature Reviews and Frontiers) are also regulated by the BAR domain superfamily proteins. In particular, we have found that I-BAR-dependent filopodia can be the source of ectosomes or plasma membrane-derived extracellular vesicles by their scission. These extracellular vesicles can transfer cellular proteins between cells, which can be engineered to deliver the protein of interest, including genome-editing enzymes.
Thus, the important questions are how BAR domain superfamily proteins are regulated and how they assemble downstream molecules, especially for those extracellular vesicles and their cargo loading and release. The role of cellular protrusions in the function of cells in higher animals, including cancer cell metastasis and neurons, is also a target of our study.
Searching for new membrane-binding proteins
Given the importance of membrane lipids as essential components of cells, we suppose there are many lipid-binding molecules that have not been clarified. We are searching for novel lipid-binding proteins using a variety of methods.
The importance of fatty acids in the membrane.
Another point for understanding the cellular membrane is the importance of fatty-acid tails of lipids. Although the importance of saturated or unsaturated lipids in nutrients is well-known, the mechanism of importance is not understood at the molecular level in cell biology. We will examine how fatty acids are important in intracellular signaling, including that for cancer, using the proteins listed above.
Application of data science to cell biology.
The above complexity of proteins and lipids results in complex cell morphology. The complex cell morphology can be divided into subcellular structures, which can be described using proteins and lipids. To understand this complexity and the connectivity between subcellular structures, we will cross-correlate protein localizations with lipid membrane localization in space and time using information technologies, including deep learning. The expected results will complement the above research and also predict cell behavior.