The role of small GTPases of the Rho/Rac family in TGF‐β‐induced EMT and cell motility in cancer

This article focuses on the role of Rho family GTPases, particularly Rac1 and Rac1b in TGF‐β‐induced epithelial‐mesenchymal transition (EMT) and EMT‐associated responses such as cell migration, invasion, and metastasis in cancer. EMT is considered a prerequisite for cells to adopt a motile and invasive phenotype and eventually become metastatic. A major regulator of EMT and metastasis in cancer is TGF‐β, and its specific functions on tumor cells are mediated beside Smad proteins and mitogen‐activated protein kinases (MAPKs) by small GTPases of the Rho/Rac1 family. Available data point to extensive signaling crosstalk between TGF‐β and various Rho GTPases, and in particular a synergistic role of Rho and Rac1 during EMT and cell motility in normal and neoplastic epithelial cells. In contrast, the Rac1‐related isoform, Rac1b, emerges as an endogenous inhibitor of Rac1 in TGF‐β signaling, at least in pancreatic carcinoma cells. Given the tumor‐promoting role of TGF‐β in late‐stage carcinomas and the intimate crosstalk of Rho/Rac1/Rac1b and TGF‐β signaling in various tumor cell responses, targeting specific Rho GTPases may allow for selective interference with prooncogenic TGF‐β responses to aid in anticancer treatments. Developmental Dynamics 247:451–461, 2018. © 2017 Wiley Periodicals, Inc.

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