Endocytic Membrane Compartmentalization by Galecti.. (GALECTCOMPART)
Endocytic Membrane Compartmentalization by Galectins
Start date: Apr 1, 2014,
End date: Mar 31, 2019
The contribution of clathrin-independent endocytosis to the cellular entry of signaling receptors, cell adhesion factors, and other cell surface molecules is well documented. However, how this process is initiated is still unknown. We have recently found that a cellular lectin, galectin-3 (Gal3), entered cells via morphologically distinct tubular structures, so-called clathrin-independent carriers (CLICs); Gal3 endocytosis was required for the uptake of the CLIC cargo CD44, a cell adhesion/migration factor; CD44 and Gal3 uptake required glycosphingolipids (GSLs); Gal3 induced tubular membrane invaginations in a GSL-dependent manner. Based on these findings we propose the groundbreaking hypothesis that Gal3 is an adaptor that clusters cargo proteins carrying defined carbohydrate modifications together with specific GSLs into nanoscale membrane environments whose mechanical properties drive the clathrin-independent formation of endocytic pits. In this program, we will first establish the compositional topology of endocytic galectin processes (Aim 1). The adaptor hypothesis will then be tested using innovative chemical biology tools (Aim 2). Quantitative models of cargo clustering and membrane shape changes will be developed on the basis of biophysical measurements and coarse grain simulations (Aim 3). Intravital imaging of endocytosis and cell migration in mice will finally explore how the functional link between galectins and GSLs contributes to wound healing in the colon (Aim 4). The molecular functions of galectins and GSLs in endocytosis — major unresolved questions in cellular membrane biology — will thereby be established, providing details from atomic arrangements via multi-molecular complexes and meso-scaled membrane domains to in vivo physiology. I am confident that this program will lead to the discovery of a new clathrin-independent endocytic mechanism by which different types of cargo are sorted to and internalized from specific membrane domains.
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