Fig. 1: Expression of the protein Scrib is required for normal cell migration. Cultured epithelial cells will normally migrate to achieve closure of an artificially induced ‘wound’ in the cell layer (left panels); however, when expression of Scrib has been knocked down (right panels), this capacity for directed migration is lost.
Reproduced from Ref. 1 © 2010 The American Society for Cell Biology
Many cells are asymmetric in shape, with correct distribution of cellular structures and components achieved via a process known as cell polarization. For example, proper function of epithelial cells depends on the establishment of apical–basal polarity, governed by the action of various proteins that reorganize the cellular infrastructure and direct the trafficking of proteins and other molecules.
Epithelial polarization is facilitated in part by the protein Scribble (Scrib) and its binding partners, and these factors also participate in the regulation of cell migration in mammalian cells. Both of these processes are also believed to depend on a cellular network of ‘intermediate filaments’ (IFs). “IFs can be linked to actin and microtubule filaments by cross-linker proteins, and work in concert with these other cytoskeletal networks to provide, among other functions, mechanical strength to the cell,” explains Walter Hunziker of the A*STAR Institute of Molecular and Cell Biology, Singapore.
Recent experiments by Hunziker’s team yielded the intriguing finding that Scrib localizes to these IFs, and subsequent work from his team has revealed that this co-localization appears to play an important role in helping cells to achieve the orientation-specificity needed for polarization and migration. They found that Scrib associates with vimentin, a core IF component, in cultured vascular and kidney epithelial cells, with this co-localization most apparent at cell–cell junctions and filaments projecting from the periphery of the nucleus. Protein–protein binding experiments confirmed that Scrib specifically interacts with both vimentin and keratin-18, another IF protein. “This was a novel finding,” says Hunziker, “as no polarity regulators had been reported to associate with IFs.”
There are important functional consequences to these interactions; cells lacking expression of either Scrib or vimentin exhibited similar defects in their capacity for directed migration (Fig. 1). These cells also appeared highly disorganized in culture, providing additional evidence that these genes work collaboratively to help cells orient themselves by promoting normal adhesion.
Subsequent experiments revealed that Scrib expression levels were closely correlated with those of vimentin, and that this IF protein helps Scrib execute its regulatory activities by stabilizing and protecting it from degradation. In fact, IFs have recently been shown to contribute to the stability of a wide variety of other proteins, including Albatross, another regulator of polarity. Hunziker and his co-workers now hope to get a better sense of how IFs and Scrib coordinate adhesion and motility in real-time. “We plan to look into the spatiotemporal dynamics of this interaction through live-cell imaging techniques,” he says.
The A*STAR-affiliated authors in this highlight are from the Institute of Molecular and Cell Biology.
