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Rho GTPases and cell migration

Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, 91 Riding House Street, London W1W 7BS, UK

View larger version (18K): [in a new window]   Fig. 1. Regulation of Rho family proteins. Most Rho proteins are active when bound to GTP, and inactive when bound to GDP. They are activated in response to extracellular signals including soluble cytokines, growth factors and extracellular matrix proteins. Activation is catalysed by exchange factors (GEFs) and inactivation by GTPase-activating proteins (GAPs). Several Rho family proteins also bind to guanine-nucleotide-dissociation inhibitors (GDIs) in the cytoplasm, and are inactive in this complex. Their activation therefore also depends on dissociation of GDI. When bound to GTP, they interact with target proteins to induce downstream responses.

View larger version (20K): [in a new window]   Fig. 2. A model for the steps of cell migration. A migrating cell extends a lamellipodium at the front. This extension is stabilized through the formation of new adhesions to the extracellular matrix. The cell body is moved forward by actomyosin-mediated contraction. Finally, the tail of the cell detaches from the substratum and retracts. Migrating cells also secrete proteases that cut up extracellular matrix proteins, and this is important for cell movement.

View larger version (21K): [in a new window]   Fig. 3. A model for Rac-induced lamellipodium extension. Rac is postulated to act through several downstream targets to regulate F-actin accumulation at the leading edge of cells, in lamellipodia. It stimulates Arp2/3-complex-induced actin polymerization by interacting with a complex of IRSp53 and WAVE proteins. This leads to the formation of a branched filament network, because the Arp2/3 complex preferentially nucleates new actin filaments on the sides of existing filaments. Rac can also induce actin filament uncapping by generating phosphatidylinositol 4,5-bisphosphate locally, generating extra sites for actin polymerization. Finally, Rac acts via PAKs to stimulate LIMK, which inhibits cofilin-induced actin depolymerization, allowing increased accumulation of polymerized actin at the leading edge of cells. PAK may also contribute to migration in other ways by regulating myosin function and focal complex turnover. Crosstalk of Rac with Cdc42 via IRSp53 and/or PAKs may regulate the level of Rac signalling.

View larger version (16K): [in a new window]   Fig. 4. Some targets for Rho linked to actin reorganization. Rho via ROCK can stimulate myosin light chain (MLC) phosphorylation through inactivation of MLC phosphatase and also probably through direct phosphorylation of MLC. ROCK together with Dia induces stress fibre formation. Dia is dependent on Src for its contribution to stress fibres and has also been reported to interact with IRSp53, which can mediate Arp2/3-complex-induced actin polymerization (see Fig. 3). ROCK can also phosphorylate a number of other target proteins that may contribute to actin reorganization, including LIMK, which inhibits cofilin-mediated actin depolymerization. Rho can also regulate the activity of PI (4)P 5-kinases (PI 5-K) to induce an increase in PtdIns(4,5)P2 levels and thereby affect capping proteins, as indicated for Rac in Fig. 3.