Situs inversus totalis refers to an inverted position of part or all of the viscera, which represents a mirror-image of the normal location, and it is a relatively rare condition that occurs in one in 4,000-8,000 people in Japan. We herein report a patient demonstrating a combination of situs inversus totalis, colon cancer with hepatic metastasis, and cholecystolithiasis, who was treated surgically. We found no expression of UVRAG mRNA in our case, thus suggesting that the UVRAG gene is partly responsible for this condition.

Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P 3 ) accumulates at the leading edge of migrating cells and works, at least partially, as both a compass to indicate directionality and a hub for subsequent intracellular events. However, how PtdIns(3,4,5)P 3 regulates the migratory machinery has not been fully elucidated. Here, we demonstrate a novel mechanism for efficient lamellipodium formation that depends on PtdIns(3,4,5)P 3 and the reciprocal regulation of PtdIns(3,4,5)P 3 itself. LL5␤, whose subcellular localization is directed by membrane PtdIns(3,4,5)P 3 , recruits the actin-cross-linking protein Filamin A to the plasma membrane, where PtdIns(3,4,5)P 3 accumulates, with the Filamin A-binding Src homology 2 domaincontaining inositol polyphosphate 5-phosphatase 2 (SHIP2). A large and dynamic lamellipodium was formed in the presence of Filamin A and LL5␤ by the application of epidermal growth factor. Conversely, depletion of either Filamin A or LL5␤ or the overexpression of either an F-actin-cross-linking mutant of Filamin A or a mutant of LL5␤ without its PtdIns(3,4,5)P 3 -interacting region inhibited such events in COS-7 cells. Because F-actin initially polymerizes near the plasma membrane, it is likely that membrane-recruited Filamin A efficiently cross-links newly polymerized F-actin, leading to enhanced lamellipodium formation at the site of PtdIns(3,4,5)P 3 accumulation. Moreover, we demonstrate that co-recruited SHIP2 dephosphorylates PtdIns(3,4,5)P 3 at the same location.Directed migration is crucial in many biological events, including morphogenesis during development, accumulation of immune cells to the site of infection, and metastasis of cancer cells. A lamellipodium (a sheet-like process composed of actin filaments) must be formed correctly at the leading edge of a cell for smooth and efficient migration. Following stimulation with a chemoattractant, phosphatidylinositol 3-kinase (PI3K) 6 is locally activated, resulting in the transient accumulation of PtdIns(3,4,5)P 3 on the leading edge of directed migrating amoebas and leukocytes (1). PtdIns(3,4,5)P 3 works, at least in part, as a cell compass that translates external signals into directed cell movement (2). However, how PtdIns(3,4,5)P 3 contributes to the appropriate formation of a lamellipodium, or conversely, how lamellipodium formation influences PtdIns(3,4,5)P 3 accumulation has not been fully elucidated. For proper lamellipodium formation, the intracellular network of actin filaments (F-actins) must be regulated both dynamically and precisely. Such networks are composed primarily of cross-linked and branched F-actins. Previous work has shown that Filamin A cross-links F-actins and is indispensable for lamellipodium formation, whereas the Wiskott-Aldrich syndrome protein family verprolin homologous (WAVE) proteins are involved in branch formation (3-5).Proteins involved in signal transduction and cytoskeletal dynamics interact with membrane phosphoinositides through their pleckstrin homology (PH) domains; such interactions * This ...

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