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G-protein signaling RAC1 in cellular process


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G-protein signaling RAC1 in cellular process

RAC1 in cellular processes

Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) is a member of the RASsuperfamily of small GTPases. It plays an essential role in control of the cell polarity,actin cytoskeleton rearrangements, protein trafficking and directed motility in a videvariety of mammalian cells [1], [2].

GTP-bound Rac1 activates a large number of effector proteins and promotesvarious signaling pathways. p21 protein (Rac1/Rac)-activated kinases 1-3 ( PAK1,PAK2, PAK3 ) are known as downstream targets of Rac1. Theassociation between the active GTP form of Rac1 and the PBD domain of PAK1-3promotes PAK1-3 autophosphorylation and activation of Mitogen-activated protein kinases8-10 ( JNK (MAPK 8-10) ) [3], [4], [5], [6], [7]. Rac1 can also activate JNK pathway via PAK-independent mechanism that involves binding and stimulation of Mitogen-activated proteinkinase kinase kinase 11 ( MLK3(MAP3K11) ) [8], [9], [10].

Rac1 is a critical regulator of NADPH oxidase activity and assembly inphagocytic cells [11]. NADPH oxidase is a multisubunit complex that containsCytochrome b-558, which is a heterodimer composed of the large Cytochrome b-245,beta polypeptide ( gp91-phox ) and small Cytochrome b-245, alpha polypeptide (p22-phox ) subunits. Activation of the oxidase is controlled by the recruitment tothe Cytochrome b-558 of such cytosolic regulatory proteins as Neutrophil cytosolicfactors 1 and 2 ( p47-phox and p67-phox ) [11]. Rac1interacts with p47-phox and p67-phox thus promoting activation of the NADPHoxidase [12], [13].

There are several known pathways through which Rac1 promotes remodeling of thecytoskeleton. One of these pathways is the stimulation by Rac1 of the actinpolymerization by activation of WAS protein family, members 1 and 2 ( WASF1(WAVE1)and WASF2 ) [14], [2], [15]. Rac1 bindsto NCK-associated protein 1 ( NckAP1 ) and Cytoplasmic FMR1 interacting protein 2( CYFIP2 ) and also promotes NCK adaptor protein 1 ( NCK1 ) binding toNckAP1. It inhibits NckAP1 and CYFIP2 binding toWASF1(WAVE1), and promotes release of the active complex of WASF1(WAVE1)and the Chromosome 3 open reading frame 10 ( HSPC300 ). ActivatedWASF1(WAVE1) stimulates Actin related protein 2/3 complex ( Arp2/3 ) thatmediates Actin cytoskeletal polymerization [16]. In addition,Rac1 binds to BAI1-associated protein 2 ( BAIAP2 ) that in turn associateswith WASF2. This stimulates Arp2/3 and leads to Actin cytoskeletalpolymerization [17], [18], [15]. In addition,Rac1 modulates cytoskeleton remodeling by activating ADP-ribosylation factorinteracting protein 2 ( POR1 ) and Phosphatidylinositol-4-phosphate 5-kinase, type1 ( PIP5KI ) [19], [20], [21].

Rac1 can directly bind to Par-6 partitioning defective 6 homolog ( PARD6) that activates Protein kinase C, zeta ( PKC-zeta ). This leads to establishmentof the cell polarity and promotes cellular transformation [22], [23], [24].

Activated Rac1 in turn can activate MCF.2 cell line derived transformingsequence-like ( DBS ), a common activator for CDC42 and RhoA [25].

Dystrophia myotonica-protein kinase ( DMPK ) and Phospholipase D1,phosphatidylcholine-specific ( PLD1 ) are also downstream targets of theRac1 [26], [27].