Epithelial cell migration is crucial for the development and regeneration of epithelial tissues. Aberrant regulation of epithelial cell migration has a major role in pathological processes such as the development of cancer metastasis and tissue fibrosis. Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCF(βTrCP) ubiquitin ligase. Failure to degrade RAPGEF2 in epithelial cells results in sustained activity of Rap1 and inhibition of cell migration induced by HGF, a potent metastatic factor. Furthermore, expression of a degradation-resistant RAPGEF2 mutant greatly suppresses dissemination and metastasis of human breast cancer cells. These findings reveal a molecular mechanism regulating migration and invasion of epithelial cells and establish a key direct link between IKKβ and cell motility controlled by Rap-integrin signaling.

The cytoskeletal mechanics and cell mechanical properties play an important role in cellular behaviors. In this study, in order to provide comprehensive insights into the relationship between different cytoskeletal components and cellular elastic moduli, we built a phasemodulated surface acoustic wave microfluidic device to measure cellular compressibility and a microfluidic micropipette-aspiration device to measure cellular Young's modulus. The microfluidic devices were validated based on experimental data and computational simulations. The contributions of structural cytoskeletal actin filament and microtubule to cellular compressibility and Young's modulus were examined in MCF-7 cells. The compressibility of MCF-7 cells was increased after microtubule disruption, whereas actin disruption had no effect. In contrast, Young's modulus of MCF-7 cells was reduced after actin disruption but unaffected by microtubule disruption. The actin filaments and microtubules were stained to confirm the structural alteration in cytoskeleton. Our findings suggest the dissimilarity in the structural roles of actin filaments and microtubules in terms of cellular compressibility and Young's modulus. Based on the differences in location and structure, actin filaments mainly contribute to tensile Young's modulus and microtubules mainly contribute to compressibility. In addition, different responses to cytoskeletal alterations between acoustophoresis and micropipette aspiration demonstrated that micropipette aspiration was better at detecting the change from actin cortex, while the response to acoustophoresis was governed by microtubule networks.

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A multiplexed superfusion system enables dynamic in vitro physiological emulation, as demonstrated by persistent circadian entrainment.