INVOLVEMENT OF RHO GTPASES IN CYTOSKELETON REGULATION - PUTATIVE ROLE IN CARCINOGENESIS

Ras-related Rho GTP-binding proteins (Cdc42Hs, Rac, and Rho proteins) have been implicated in the regulation of actin cytoskeleton and in the assembly of integrin receptors which control the morphology, adhesion, and motility of cells; an actual Rho signalling cascade was shown in fibroblasts Swiss 3T3 cells to regulate the formation of cellular actin structures in response to growth factors. Thus, fillopodia, ruffles, lamellipodia, actin stress fibers and focal adhesions were shown to be controlled in turn and respectively by activated Cdc42Hs, Rac1, and Rho1 proteins. Recent studies led to the identification of several proteins acting along this signalling pathway by regulating the state of activation of the Rho proteins (proteins with exchange-factor activity), or by interacting with activated GTP-bound Rho proteins as actual effectors of these proteins. Several kinases, of which actual precise function remains unclear, have been suspected to belong to this latter category. A direct involvement of RhoA and RhoB proteins has also been suspected in the progress of cell cycle by interaction with the actomyosin system. But, surprisingly, it is another Rho family member, Rac, that was recently forming activity in fibroblasts cells. Lastly, many oncogenic proteins with Rho/Rac exchange-factor activity and Db1 domain have been recently characterized. Thus, Tiam1 activator of Rac was shown to regulate the invasive capacity of RacV12 expressing cells. These experimental observations illustrate the existence of a new signalling pathway Ras --> Rac leading to transformation or invasiveness, coordinated with, but parallel to, the classical Ras --> Raf --> MAP kinase pathway.