Tiam1/Rac Signalling and Tumourigenesis In Vivo

Tiam1 (for T-lymphoma invasion and metastasis protein) belongs to the GEF family of proteins and selectively activates Rac in response to growth factors and cell-substrate interactions.  Precisely how these upstream events engage the Tiam1-Rac signaling module is unclear.  One possible mechanism is suggested by the observed association of Tiam1 with the second messenger Ras through a Ras-binding domain (RBD).  Activated Ras and Tiam1 then cooperate to activate Rac (Lambert et al., Nature Cell Biol 2002; 4: 621).  Significantly, mice deficient for Tiam1 are resistant to the formation of skin tumours induced by topical application of chemical carcinogens and consequent oncogenic activation of the c-Ha-Ras gene (Malliri et al., Nature 2002; 417: 867).  Tiam1-deficient tumours were not only fewer but also smaller than wild-type tumours and this correlated with increased apoptosis and reduced proliferation in carcinogen-exposed Tiam1-deficient mice.

Tiam1 is also a potent modifier of intestinal tumourigenesis (Malliri et al., J Biol Chem 2006; 281: 543).  The majority of intestinal tumours are caused by mutations in the canonical Wnt signaling pathway, leading to aberrant expression of Wnt-responsive genes.  Tiam1 is a Wnt-responsive gene, and is expressed in crypts of the adult mammalian intestine as well as in adenomas from patients and Min (multiple intestinal neoplasia) mice.  In each of these settings, the Wnt pathway is activated.  Further, by comparing tumour development in Min mice expressing or lacking Tiam1, it was found that Tiam1 deficiency significantly reduces the formation as well as growth of polyps in vivo (Malliri et al., J Biol Chem 2006; 281: 543).

 

Interactions of Ras and Rac pathways figure

Figure 2 LegendInteractions of Ras and Rac pathways in tumourigenesis based on chemical skin carcinogenesis of Tiam1 mutant mice.Tiam1-deficient mice develop fewer and smaller Ras-induced skin tumours than wild-type mice. This is related to the positive effects of Tiam1/Rac signaling on cell survival and proliferation. However, Tiam1-deficient tumours progressed more frequently to malignancy. This can be explained by in vitro and in vivo results showing that high levels of Ras signaling (Ras↑↑), as seen in advanced skin malignancies, down-regulates Tiam1 expression and thereby Rac activity which is required for cell-cell adhesion.