Control of Epithelial Cell Migration and Invasion by the IKKβ- and CK1α-Mediated Degradation of RAPGEF2

Epithelial cell migration is crucial for the develop- ment and regeneration of epithelial tissues. Aberrant regulation of epithelial cell migration has a major role in pathological processes such as the develop- ment 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-b and casein kinase-1a and consequently degraded by the proteasome via the SCFbTrCP ubiq- uitin ligase. Failure to degrade RAPGEF2 in epithelial cells results in sustained activity of Rap1 and inhibi- tion 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 molecu- lar mechanism regulating migration and invasion of epithelial cells and establish a key direct link be- tween IKKb and cell motility controlled by Rap- integrin signaling.