Cytoskeleton remodeling - CDC42 in cellular processes

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 [1], [2], [3], [4]. 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 [5], [6]. The association between the active GTP form of CDC42 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 rearrangements and cell motility [8].

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

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

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 [3], [12], [13], [14].

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

CDC42 induces actin cytoskeleton changes also by activating Wiskott-Aldrich syndrome (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 filopodia formation [18], [19].

And finally, CDC42 promotes cytoskeleton remodeling by binding to CDC42 effector 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 leads to establishment of cell polarity and promotes cellular transformation [22], [23], [24]. Also CDC42 induces cellular transformation by associating with the Coatomer protein complex, subunit gamma 2 (COPG2) [25].

References:

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