Caveolin and Rhofamily GTPases

Rho GTPases participate in the regulation of polarity, microtubule dynamics and cell shape, the latter property being regulated by the Rho GTPases adjusting the organization of the actin cytoskeleton. For example, Cdc42 induces filopodia, Rac induces lamellipodia, and Rho induces focal adhesion and associated stress fibers [13] (Fig. 9.2).

Rho GTPases are a group of molecular switches which control complex cellular processes. They cycle between two conformational states: one state is bound to GTP (the "active" state), and the other state is bound to GDP (the "inactive" state), although both states hydrolyze GTP to GDP. The active GTPases recognize target proteins and generate a response until GTP hydrolysis returns the switch to the GDP state.

In order to drive the processes in precise fashion, the activities of Rho GTPases

Caveolin Focal Adhesion Dynamics

Fig. 9.2 Rho GTPases and caveolae. Rho GTPases induce morphological changes via the formation of filopodia, lamellipodia, focal adhesion and actin stress fiber. Rho GTPases are recruited into the caveolae, where their activities are regulated by caveolin-1. Caveolin-1 can interact with the integrin a subunit and Fyn, leading to stable focal adhesion formation.

Fig. 9.2 Rho GTPases and caveolae. Rho GTPases induce morphological changes via the formation of filopodia, lamellipodia, focal adhesion and actin stress fiber. Rho GTPases are recruited into the caveolae, where their activities are regulated by caveolin-1. Caveolin-1 can interact with the integrin a subunit and Fyn, leading to stable focal adhesion formation.

must be tightly controlled spatiotemporally within the cells. Recent studies have suggested that the function of Rho GTPases may be deeply related with caveolae or lipid rafts. In endothelial cells, sucrose gradient density centrifugation studies have revealed that a significant proportion of RhoA and Cdc42 are localized within caveolae-enriched membrane domains. Moreover, caveolin-1 is directly bound with RhoA but not with Cdc42 [6]. In neonatal rat cardiomyocytes, the initiation and transduction of stretch-induced RhoA and Rac1 activation requires caveolar compartment [7]. However, in unstretched cardiomyocytes RhoA and Rac1 were detected in both the caveolae and noncaveolar fractions. RhoA and Rac1 was activated within 4 minutes by stretching, then inactivated after 15 minutes, and subsequently became dissociated from the caveolae. In addition, treatment with methyl-b-cyclodextrin (mbCD), a caveolae-disrupting agent, inhibits the stretching-induced RhoA and Rac1 activation [7]. Moreover, integrins influence the targeting of Rac and Rho GTPases to the plasma membrane via lipid raft or caveolae and their coupling to downstream effector molecules [14]. In migrating cells, integrins interact with caveolae or lipid rafts to mobilize the activated GTP-bound Rac and Rho to the plasma membrane.

As illustrated in Figure 9.2, caveolin-1 is involved in the regulation of cellular morphological changes via the modulation of Rho GTPases activity. Senescent human diploid fibroblasts (HDFs) show an altered cellular morphology of flattened and enlarged cell shape, in contrast to the small, spindle shape of young cells. In senescent HDFs, the activities of Rac1 and Cdc42 are significantly increased, and overexpression of active Rac1 and Cdc42 in young HDFs resulted in senescence-like morphological changes. We have observed that the active forms of Rac1 and Cdc42 are localized in caveolae and interact directly with caveolin-1 in senescent HDFs [5]. Interestingly, it has been suggested that caveolin-1 is required for filopodia formation, which may enhance the invasive ability of lung adenocarcinoma cells, though the level of caveolin itself is relatively low [15]. These results suggest that caveolin might involve the determination of cell shape and migration through polarity arrangement and the regulation of Rho GTPases activity.

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