The Role of the Guanine Nucleotide Exchange Factor Tiam1 in Cellular Migration, Invasion, Adhesion and Tumor Progression

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Abstract
While advances in molecular genetics have provided new insights into molecular alterations that lead to the development of many tumors, including breast carcinoma, the genetic and epigenetic alterations that result in metastatic spread of the disease, from which afflicted patients ultimately succumb, are much more poorly understood. Important biologic processes in the development of metastasis include increased migration and invasion of tumor cells. While the regulation of these processes is complex, they are controlled in part by small G proteins of the Rho family, including Rho, Rac, and Cdc42, that are involved in cytoskeletal organization. These proteins, active when bound to GTP, are, in turn, regulated by guanine nucleotide exchange factors (GNEFs) and guanine nucleotide activating proteins. The GNEF Tiam1 catalyzes nucleotide exchange for Rac in vivo, and Rac, Cdc42 and Rho in vitro. Tiam1 was identified first in 1994 by in vitro selection for invasiveness in T-lymphoma cells. Accordingly, Tiam1 has been shown to increase invasion in T-lymphoma cells, as well as to increase cellular migration in fibroblasts, and to promote motility in some neuronal cells. In contrast, Tiam1 has been demonstrated to increase cellular adhesion in some epithelial cell populations. Thus, Tiam1 has multiple roles in regulating cellular functions, likely dependent on the cell type, the substratum, transformation status of the cells, and the activation state of small G proteins in a given cell. Increasing evidence has focused on Tiam1’s regulation, as well as Tiam1’s role in cancer progression and metastasis. Recent results from other laboratories and ours have demonstrated that increased Tiam1 expression correlates with grade of breast cancer in humans and metastatic potential of human breast carcinoma cell lines in nude mice. This review will discuss Tiam1’s cellular functions and methods of regulation, and will highlight Tiam1’s contribution to cancer progression and metastasis.