CD44 is a cell surface adhesion molecule for hyaluronan and is implicated in tumor invasion and metastasis. Proteolytic cleavage of CD44 plays a critical role in the migration of tumor cells and is regulated by factors present in the tumor microenvironment, such as hyaluronan oligosaccharides and epidermal growth factor. However, molecular mechanisms underlying the proteolytic cleavage on membranes remain poorly understood. In this study, we demonstrated that cholesterol depletion with methyl-␤-cyclodextrin, which disintegrates membrane lipid rafts, enhances CD44 shedding mediated by a disintegrin and metalloproteinase 10 (ADAM10) and that cholesterol depletion disorders CD44 localization to the lipid raft. We also evaluated the effect of long term cholesterol reduction using a statin agent and demonstrated that statin enhances CD44 shedding and suppresses tumor cell migration on a hyaluronan-coated substrate. Our results indicate that membrane lipid organization regulates CD44 shedding and propose a possible molecular mechanism by which cholesterol reduction might be effective for preventing and treating the progression of malignant tumors.CD44 is a cell surface receptor for several extracellular matrix components, including hyaluronan (1), and is implicated in a wide variety of biological processes, including cell migration (2) and tumor metastasis (3). The migratory properties of invasive tumor cells are affected both by the interaction between their adhesion molecules and the surrounding extracellular matrices and by growth factor signaling (4). The proteolytic ectodomain cleavage and release (shedding) of membrane proteins is a critical regulatory step in both physiological and pathological processes (5, 6).Recently, physiological inducers of CD44 shedding have been identified; hyaluronan small fragments, frequently detected in association with pathological conditions including cancer (7), induce CD44 shedding from tumor cells (8). Intracellular signaling via Rac GTPase, elicited by CD44 engagement, leads to ADAM 2 (a disintegrin and metalloproteinase)-mediated CD44 shedding and tumor cell migration (9). A prominent abnormality of tumor cells such as gliomas is the overexpression of the EGF receptor (10), and EGF induces the shedding of CD44 (11). Although the molecular mechanisms underlying CD44 shedding induced by spatio-temporally ordered intracellular signaling in the tumor microenvironment have been partly clarified (9, 11), the mechanism that triggers CD44 shedding on the membrane is not yet understood.Lipid rafts, which are microdomains of the plasma membrane that are rich in cholesterol and sphingolipids (12), are thought to exhibit a liquid-ordered phase floating in the liquid-disordered matrix of the plasma membrane. Recent studies have confirmed the importance of lipid rafts and their associated proteins, including CD44, in cancer progression (13). A number of reports have shown that CD44 is present in lipid rafts (14 -18). Recently, several reports have demonstrated that lipid rafts play a cruci...

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This paper reviews diverse capabilities offered by modern electron microscopy techniques in studying fine structures of nanoporous crystals such as zeolites, silica mesoporous crystals, metal organic frameworks and yolk-shell materials. For the case of silica mesoporous crystals, new approaches that have been developed recently to determine the three-dimensionally periodic average structure, e.g., through self-consistent analysis of electron microscope images or through consideration of accidental extinctions, are presented. Various structural deviations in nanoporous materials from their average structures including intergrowth, surface termination, incommensurate modulation, quasicrystal and defects are demonstrated. Ibidem observations of the scanning electron microscope and atomic force microscope give information about the zeolite-crystal-growth mechanism, and an energy for unstitching a building-unit from a crystal surface is directly observed by an anatomic force microscope. It is argued how these observations lead to a deeper understanding of the materials.