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toxins that activate rho
transformation is more obviously appreciated by the observation that many
GEFs are well-established products of oncogenes. This category includes Vav,
(Olson et al., 1996), Lbc (Zheng et al., 1995), Dbl (Hart et al., 1991), TIAM-1
(Michiels et al., 1995), and many others (Jaffe and Hall, 2002). Accordingly, it
was shown that mice, which are deficient in the Rac GEF TIAM, are resistant
to Ras-induced skin tumours (Malliri et al., 2002).
Recently, an important connection between the actin cytoskeleton and
transcriptional activation was described. It was shown that LIM Kinase and
Diaphanous cooperate to regulate serum responsive factor and actin dynam-
ics (Geneste et al., 2002). It has been known for many years that a dynamic
actin cytoskeleton is needed for the cleavage of a dividing cell into two daugh-
ter cells. Moreover, it has been shown in many different cell systems that Rho
GTPases are involved in cell division. Several Rho effectors, including Rho
kinase (ROCK) and citron kinase, are localised at cleavage furrows (Chevrier
et al., 2002). Moreover, Myosin II, which is phosphorylated by Rho kinase, is
an essential motor for cytokinesis (Matsumura et al., 2001). Rho kinase has
been identified as a component of the centrosome. It is required for posi-
tioning of the centrosomes, which play a role in cell division as well as in cell
motility.
RHOPROTEINS AS TARGETS OF BACTERIAL TOXINS
During the last few years, it has been recognised that Rho proteins are ma-
jor eukaryotic targets for various bacterial protein toxins. Some toxins block
the functions of Rho GTPases by covalent modification. For example, C3-
like toxins from C. botulinum, C. limosum, and S. aureus, which share 30 to
70% aminoacid sequence identity, ADP-ribosylate small GTPases of the Rho
family (e.g., at Asn41 of RhoA [Sekine et al., 1989]) and inactivate them. The
prototype of these small toxins (23–30 kDa) is the Clostridium botulinum C3
toxin, which ADP ribosylates RhoA, B, and C (Aktories et al., 1987; Wilde
and Aktories, 2001).
It was assumed that Rho function is blocked due to sterical hinderance
of the GTPase-effector interaction, because the modified residue is located
close to the effector region. However, recent studies indicate that ADP-
ribosylated Rho is still able to interact with at least some effectors (Genth
et al., 2003b). However, the rate of activation of Rho by exchange factors
(e.g., Lbc) is diminished by ADP-ribosylation (Genth et al., 2003b), and it was
suggested that ADP-ribosylation prevents the conformational change, occur-
ring subsequently with GDP/GTP exchange (Genth et al., 2003a). Moreover,
ADP-ribosylated Rho is released from membranes and forms a tight complex