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Cytoskeleton remodeling CDC42 in cellular processes


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Cytoskeleton remodeling CDC42 in cellular processes

CDC42 in cellular processes

Cell division cycle 42 ( CDC42 ) is a member of the RAS superfamily of smallGTPases and plays an essential role in control of cell polarity, actin cytoskeletonrearrangements, protein trafficking and directed cell movements in a vide variety ofmammalian cells [1], [2], [3], [4].CDC42 is activated by GEFs (Guanine Nucleotide Exchange Factors), and repressed byGAPs (GTPase- Activating Proteins).

GTP-bound CDC42 activates a large number of effector proteins and promotesdifferent signaling pathways. p21 protein (Cdc42/Rac)-activated kinases 1-4 ( PAK1, PAK2, PAK3, PAK4 ) are known downstream targets of CDC42[5], [6]. The association between the active GTP form ofCDC42 and the PBD domain of PAK1-4 promotes PAK1-4 autophosphorylation [7]. All four PAKs are capable to promote Mitogen-activated protein kinases 8-10 (JNK (MAPK 8-10) ) signaling activation that leads to cytoskeletal rearrangementsand cell motility [8].

CDC42 can activate JNK pathway also by binding and stimulation ofMitogen-activated protein kinase kinase kinase 11 ( MLK3(MAP3K11) ) [9].

Binding of CDC42 small effector 1 ( SPEC1 ) to CDC42 suppressesCDC42 -induced JNK activation and cytoskeleton remodeling [10], [11].

CDC42 promotes changes in actin cytoskeleton by several pathways. CDC42activates PAK1, PAK4 and CDC42 binding protein kinase alpha (MRCKalpha ) which phosphorylate LIM domain kinases 1 and 2 ( LIMK1 andLIMK2 ) and they subsequently phosphorylate and inhibit Cofilin and Destrin(actin depolymerizing factor) ( Destrin ). This leads to actin polymerization andstimulation of filopodia and stress fibers formation [12], [13],[3], [14].

PAK3 stimulated by CDC42 induces v-raf-1 murine leukemia viral oncogenehomolog 1 ( c-Raf-1 ) signaling [15].

CDC42 induces actin cytoskeleton changes also by activating Wiskott-Aldrichsyndrome ( WASP ) and Wiskott-Aldrich syndrome-like ( N-WASP ) [16], [17], which binds to Actin related protein 2/3 complex (Arp2/3 ) and this leads to Actin cytoskeletal polymerization and filopodiaformation [18], [19].

And finally, CDC42 promotes cytoskeleton remodeling by binding to CDC42effector proteins 2 and 3 ( CEP2 and CEP3 ) [20], [21].

CDC42 can directly bind to Par-6 partitioning defective 6 homolog (PARD6 ) which activates Protein kinase C, zeta ( PKC-zeta ), and this leadsto establishment of cell polarity and promotes cellular transformation [22],[23], [24]. Also CDC42 induces cellular transformation byassociating with the Coatomer protein complex, subunit gamma 2 ( COPG2 ) [25].