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 ( MLK3(MAP3K11) ) .
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 , .
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 ( COPG2 ) .