The bacterial pathogen Salmonella typhimurium triggers host cell signa
ling pathways that lead to cytoskeletal and nuclear responses required
for pathogenesis. Here, the role of the small guanosine triphosphate
(GTP)-binding protein CDC42Hs in these responses was examined. Express
ion of a dominant interfering mutant of CDG42 (CDC42HsN17) prevented S
. typhimurium-induced cytoskeletal reorganization and subsequent macro
pinocytosis and bacterial internalization into host cells. Cells expre
ssing constitutively active CDC42 (CDC42HsV12) internalized an S. typh
imurium mutant unable to trigger host cell responses. Furthermore, exp
ression of CDC42HsN17 prevented S. typhimurium-induced JNK kinase acti
vation. These results indicate that CDC42 is required for bacterial in
vasion and induction of nuclear responses in host cells.