CDC42 in cellular processes
Cell division cycle 42 (CDC42) is a member of the RAS
superfamily of small GTPases and plays an essential role in control of cell polarity,
actin cytoskeleton rearrangements, protein trafficking and directed cell movements in a
vide variety of mammalian cells , , , . CDC42 is activated by GEFs (Guanine
Nucleotide Exchange Factors), and repressed by GAPs (GTPase- Activating Proteins).
GTP-bound CDC42 activates a large number of effector
proteins and promotes different signaling pathways. p21 protein (Cdc42/Rac)-activated
kinases 1-4 (PAK1, PAK2,
PAK3, PAK4) are known
downstream targets of CDC42 , . The association between the active GTP form of
CDC42 and the PBD domain of PAK1-4 promotes PAK1-4
autophosphorylation . All four PAKs are capable to promote
Mitogen-activated protein kinases 8-10 (JNK (MAPK 8-10))
signaling activation that leads to cytoskeletal rearrangements and cell motility .
CDC42 can activate JNK pathway also by binding and
stimulation of Mitogen-activated protein kinase kinase kinase 11
Binding of CDC42 small effector 1 (SPEC1) to
CDC42 suppresses CDC42-induced
JNK activation and cytoskeleton remodeling , .
CDC42 promotes changes in actin cytoskeleton by several
pathways. CDC42 activates PAK1,
PAK4 and CDC42 binding protein kinase alpha
(MRCKalpha) which phosphorylate LIM domain kinases 1 and 2
(LIMK1 and LIMK2) and they
subsequently phosphorylate and inhibit Cofilin and Destrin
(actin depolymerizing factor) (Destrin). This leads to actin
polymerization and stimulation of filopodia and stress fibers formation , , , .
PAK3 stimulated by CDC42
induces v-raf-1 murine leukemia viral oncogene homolog 1
(c-Raf-1) signaling .
CDC42 induces actin cytoskeleton changes also by
activating Wiskott-Aldrich syndrome (WASP) and
Wiskott-Aldrich syndrome-like (N-WASP) , , which binds to Actin related protein 2/3 complex
(Arp2/3) and this leads to Actin
cytoskeletal polymerization and filopodia formation , .
And finally, CDC42 promotes cytoskeleton remodeling by
binding to CDC42 effector proteins 2 and 3 (CEP2 and
CEP3) , .
CDC42 can directly bind to Par-6 partitioning defective 6
homolog (PARD6) which activates Protein kinase C, zeta
(PKC-zeta), and this leads to establishment of cell polarity
and promotes cellular transformation , , . Also CDC42 induces cellular transformation by
associating with the Coatomer protein complex, subunit gamma 2
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