The Rho Guanine Nucleotide Exchange Factor Syx Regulates the Balance of Dia and ROCK Activities To Promote Polarized-Cancer- Cell Migration

The role of RhoA in promoting directed cell migration has been complicated by studies showing that it is activated both in the front and the rear of migrating cells. We report here that the RhoA-specific guanine nucleotide exchange factor Syx is required for the polarity of actively migrating brain and breast tumor cells. This function of Syx is mediated by the selective activation of the RhoA downstream effector Dia1, the subsequent reorganization of microtubules, and the downregulation of focal adhesions and actin stress fibers. The data argue that directed cell migration requires the precise spatiotemporal regulation of Dia1 and ROCK activities in the cell. The recruitment of Syx to the cell membrane and the subsequent selective activation of Dia1 signal-ing, coupled with the suppression of ROCK and activation of cofilin-mediated actin reorganization, plays a key role in establish-ing cell polarity during directed cell migration. Rho GTPases (including RhoA, Rac1, and Cdc42) are key me-diators of cytoskeletal dynamics (1). In concert with adhesion receptors and polarity complexes, Rho GTPases regulate apico-basal polarity and epithelial cell adhesion, or front-end polarity and directed cell migration (2–4). Rac1 and Cdc42 activities are associated with actin reorganization and membrane protrusion at the leading cell edge, promoting either directed cell migration or cell-cell contact (1, 2, 4, 5). RhoA is linked with either a strength