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Cell Motility: A glycolipid applies the brake

The glycan components of glycolipids stretch into the extracellular space where they interact with other carbohydrates and membrane components such as receptors and signal transducers to control cell adhesion and signaling. Glycosphingolipids — also called ceramides — consist of a saccharide linked to the fatty amino alcohol sphingosine, which in turn, is bound to a fatty acid. Membrane proteins and glycosphingolipids have been proposed to form membrane microdomains or glycosynapses that could influence the phosphorylation state of membrane tyrosine kinases. One such kinase is Met, a key regulator of cellular motility which is overactive in malignant cells. A study by Hakomori and coworkers in The Journal of Biological Chemistry now reveals that the interaction of GM2 with other components of the glycosynapse contributes to the regulation of Met in malignant and normal cells.

The authors observed that in the bladder epithelial cell line HCV29, Met was activated by its ligand, hepatocyte growth factor (HGF). However, in the bladder cancer cell line YTS, Met activity was high even in the absence of HGF. Analysis of the cell membranes by confocal microscopy and immunoprecipitation revealed that in both cell lines Met was associated with the glycosphingolipid GM2. In HCV29 cells GM2 was also associated with the tetraspanin membrane protein CD82, but in YTS cancer cells CD82 was absent. Expression of CD82 in YTS cells restored the dependence of Met activation on HGF as long as GM2 synthesis was not blocked. Conversely, in HVC29 cells CD82 knock-down by RNAi led to HGF-independent Met activation and cell motility. These findings indicate that the CD82-GM2 complex blocks the activation of Met by HGF.

Additionally, the authors found that the CD82-GM2 complex attenuates the functional interaction ("cross-talk") of integrin 31 with Met, further decreasing Met activation through cell adhesion to the extracellular matrix protein laminin. This may provide a second means by which GM2 regulates cell motility. Using in vitro binding assays, Hakomori and coworkers found that CD82 did not interact with the glycolipids Gb4 or GM3, which emphasizes the specificity of CD82-GM2 interaction.

This study presents an intriguing example of how cell surface carbohydrate structures can control of cell motility. The authors hypothesize that the carbohydrate portion of GM2 and N-glycans on the highly glycosylated extracellular domain of CD82 interact to form the CD82-GM2 complex, the details of which remain to be further investigated.

Author: Mirko von Elstermann