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Sustained canonical Wnt signaling requires the inhibition of glycogen synthase kinase 3 (GSK3) activity by sequestration of GSK3 inside multivesicular endosomes (MVEs). Here, we show that Wnt signaling is increased by the lysosomal inhibitor chloroquine, which causes accumulation of MVEs. A similar MVE expansion and increased Wnt responsiveness was found in cells deficient in presenilin, a protein associated with Alzheimer's disease. The Wnt-enhancing effects were entirely dependent on the functional endosomal sorting complex required for transport (ESCRT), which is needed for the formation of intraluminal vesicles in MVEs. We suggest that accumulation of late endosomal structures leads to enhanced canonical Wnt signaling through increased Wnt-receptor/GSK3 sequestration. The decrease in GSK3 cytosolic activity stabilized cytoplasmic GSK3 substrates such as β-catenin, the microtubule-associated protein Tau, and other proteins. These results underscore the importance of the endosomal pathway in canonical Wnt signaling and reveal a mechanism for regulation of Wnt signaling by presenilin deficiency.
Pubmed ID: 23122960
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The Center for Bio-Image Informatics is an interdisciplinary research effort between Biology, Computer Science, Statistics, Multimedia and Engineering. The overarching goal of the center is the advancement of human knowledge of the complex biological processes which occur at both cellular and sub-cellular levels. the center employs and develops cutting edge techniques in the fields of imaging, pattern recognition and data mining. Research also focuses on development of new information processing techniques which can afford us a better understanding of biological processes depicted in microscopy images of cells and tissues, specifically on the distributions of biological molecules within these samples. This is achieved by borrowing methods for information processing at the sensor level to enable high speed and super-resolution imaging. By applying pattern recognition and data mining methods to bio-molecular images, full automation of both the extraction of information and the construction of statistically-sound models of the processes depicted in those images was possible. At the heart of the center's reseach is the BISQUE system, an online repository for multidimensional bio-images, and testbed for new research techniques and methods. BISQUE: Online Semantic Query User Environment is an online database for managing up to 5 dimensional scientific images with associated metadata and a flexible, collaborative tagging system. Currently the system has more than 85,000 user-provided tags and 128006 2-D planes from over 6,000 biological images. BISQUE is much more than just a repository for scientific images- the system provides resources for complex scientific analysis over images, result visualization, user-extensible modules, customized organization of images, advanced search features, graphical annotations, textual annotations and compatible client-side applications. Sponsors: This work is supported in part by an NSF infrastructure award No. EIA-0080134 and IIS-0808772.
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