Rap1 regulates hepatic stellate cell migration through the modulation of RhoA activity in response to TGF­ß1.

Although the migration of hepatic stellate cells (HSCs) is important for hepatic fibrosis, the regulation of this migration is poorly understood. Notably, transforming growth factor (TGF)­ß1 induces monocyte migration to sites of injury or inflammation during the early phase, but inhibits cell migration during the late phase. In the present study, the role of transforming protein RhoA signaling in TGF­ß1­induced HSC migration was investigated. TGF­ß1 was found to increase the protein and mRNA levels of smooth muscle actin and collagen type I in HSC­T6 cells. The level of RhoA­GTP in TGF­ß1­stimulated cells was significantly higher than that in control cells. Furthermore, the phosphorylation of cofilin and formation of filamentous actin (F­actin) were more marked in TGF­ß1­stimulated cells than in control cells. Additionally, TGF­ß1 induced the activation of nuclear factor­κB, and the expression of extracellular matrix proteins and several cytokines in HSC­T6 cells. The active form of Rap1 (Rap1 V12) suppressed RhoA­GTP levels, whereas the dominant­negative form of Rap1 (Rap1 N17) augmented RhoA­GTP levels. Therefore, the data confirmed that Rap1 regulated the activation of RhoA in TGF­ß1­stimulated HSC­T6 cells. These findings suggest that TGF­ß1 regulates Rap1, resulting in the suppression of RhoA, activation of and formation of F­actin during the migration of HSCs.