The guanine nucleotide exchange factor Tiam1: a Janus-faced molecule in cellular signaling

Abstract

The Rho family of GTPases consists of several small proteins that have been described as molecular switches, playing important roles in a wide variety of fundamental cellular processes and in human diseases such as cancer. These proteins, active in the GTP conformation and inactive in the GDP form, are in turn regulated by guanine nucleotide exchange factors (GEFs), guanine nucleotide activating proteins (GAPs) and guanine dissociation inhibitors (GDIs). Two decades ago, Tiam1 (T-lymphoma invasion and metastasis) was identified as a GEF specific for Rac1 activation, but also for Cdc42 and in a lesser extent RhoA. Acting principally upstream of Rac1, Tiam1 is mainly involved in the regulation of Rac1 mediated signaling pathways including cytoskeletal activities, cell polarity, endocytosis and membrane trafficking, cell migration, adhesion and invasion, cell growth and survival, metastasis and carcinogenesis. However, given the large number of protein interaction domains found in its structure, it is possible that Tiam1 affects cellular processes in another way than through its GEF activity by interactions with other signaling proteins. Due to its functional diversity, Tiam1 is involved in multiple steps of tumorigenesis. As its name suggests, Tiam1 has been shown to increase T-cell lymphoma invasion and metastasis. It also promotes migration of fibroblasts, neuronal and cancer cells. On the contrary, Tiam1-induced cell adhesion has also been described, as opposed to cell migration. Moreover, studies indicate that Tiam1 is involved in both anti-apoptotic and pro-apoptotic mechanisms. While increasing evidence has demonstrated Tiam1's contribution to tumorigenesis and metastasis, others suggest that Tiam1 could have anti-cancer properties. In the present review, we discuss the current knowledge about the controversial roles of Tiam1 in cellular signaling. In particular, we will focus on Tiam1's regulation, its biological functions and implication in cancer.

Keywords: DH; Dbl homology; GAP; GDI; GDP; GEF; GTP; GTPase-activating protein; Guanine nucleotide exchange factors; JIP/IB2; PH; RBD; Rac1; Ras binding domain; Rho-GTPases; STEF; Sif and Tiam1-like exchange factor; Signaling; T-lymphoma invasion and metastasis; Tiam1; Tumorigenesis; c-Jun N-terminal kinase-interacting protein/islet-brain 2; guanine dissociation inhibitor; guanine nucleotide-exchange factor; guanosine diphosphate; guanosine triphosphate; pleckstrin homology.