Yamada lab @UC Davis
Our laboratory is interested in how mammalian cells touch, feel and work together to form multi-cellular tissues and organs. Cell-to-cell interactions are mediated by cell adhesion molecules and the cytoskeleton, and carefully regulated. Since abnormal cell adhesion is common in diseases like cancer, understanding of cell adhesion should lead to novel treatments.
Using biophysical and cell biological approaches, we are trying to tease out the mechanisms involved in the regulation of cell adhesion. One approach is to analyze cell interactions in a physiologically relevant three-dimensional matrix using a live-cell confocal microscope system (see our movies on Youtube). In addition, we are analyzing the regulation of cell adhesion strength using microfabricated force sensor and atomic force microscopy. Our goal is to understand how normal and cancer cells interact with each other to regulate their migration through surrounding extracellular matrix and neighboring cells. Our unique experimental approaches provide new perspectives on how proteins assemble to generate physical and dynamic cell adhesions essential for morphogenesis and metastasis.
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Force-sensitive protein interactions
Physical force emerged as a key regulator of tissue homeostasis, and plays an important role in embryogenesis, tissue regeneration, and disease progression. Currently, the details of protein interactions under elevated physical stress are largely missing, therefore, preventing fundamental, molecular understanding of mechano-transduction. This is in part due to the isolation of protein complexes under force-bearing condition is impossible using traditional solution biochemistry. Instead, our innovative biochemical analysis is based on in situ proximal biotin labeling using a promiscuous biotin ligase with a cell stretch device that promotes the formation of force-sensitive complexes. Using this approach, we identified a unique force-sensitive protein interaction surrounding α-catenin [Ueda el al.]. Based on our innovative strategy, we are in an ideal position to uncover the composition of force-sensitive complexes, a critical first step for understanding the molecular basis of mechano-transduction.
Self-contact induced membrane fusion
Biological membranes are frequently remodeled via membrane fusion and fission, a crucial requirement during tissue development and homeostasis. While intra-cellular membrane fusion is ubiquitous and well-studied, fusion between plasma membranes is rare and thought to be reserved for specialized cells. Using innovative micro-fabricated substrates, we demonstrated that mammalian epithelial and endothelial cells are highly fusogenic even in the absence of fusion-inducing factors [Sumida and Yamada]. However, this plasma membrane fusion is strictly limited to self-contacts, i.e., two extending and adhering membrane protrusions from a single cell, and not between two membrane protrusions from neighboring cells. Our intriguing observation suggests that epithelial and endothelial cells have a remarkably efficient molecular complex to fuse plasma membranes, and are capable of discriminating self- from neighboring cell-cell contacts. The obvious consequence of defective self-awareness is unwanted cell-to-cell fusion, a phenomenon observed in cancer cells and macrophages in tuberculosis. We are in process of identifying key molecules required for this unique membrane fusion.