G-protein signaling - RAC1 in cellular process

RAC1 in cellular processes

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

GTP-bound Rac1 activates a large number of effector proteins and promotes various signaling pathways. p21 protein (Rac1/Rac)-activated kinases 1-3 (PAK1, PAK2, PAK3) are known as downstream targets of Rac1. The association between the active GTP form of Rac1 and the PBD domain of PAK1-3 promotes PAK1-3 autophosphorylation and activation of Mitogen-activated protein kinases 8-10 (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 protein kinase kinase kinase 11 (MLK3(MAP3K11)) [8], [9], [10].

Rac1 is a critical regulator of NADPH oxidase activity and assembly in phagocytic cells [11]. NADPH oxidase is a multisubunit complex that contains Cytochrome 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 to the Cytochrome b-558 of such cytosolic regulatory proteins as Neutrophil cytosolic factors 1 and 2 (p47-phox and p67-phox) [11]. Rac1 interacts with p47-phox and p67-phox thus promoting activation of the NADPH oxidase [12], [13].

There are several known pathways through which Rac1 promotes remodeling of the cytoskeleton. One of these pathways is the stimulation by Rac1 of the actin polymerization by activation of WAS protein family, members 1 and 2 (WASF1(WAVE1) and WASF2) [2], [14], [15]. Rac1 binds to NCK-associated protein 1 (NckAP1) and Cytoplasmic FMR1 interacting protein 2 (CYFIP2) and also promotes NCK adaptor protein 1 (NCK1) binding to NckAP1. It inhibits NckAP1 and CYFIP2 binding to WASF1(WAVE1), and promotes release of the active complex of WASF1(WAVE1) and the Chromosome 3 open reading frame 10 (HSPC300). Activated WASF1(WAVE1) stimulates Actin related protein 2/3 complex (Arp2/3) that mediates Actin cytoskeletal polymerization [16]. In addition, Rac1 binds to BAI1-associated protein 2 (BAIAP2) that in turn associates with WASF2. This stimulates Arp2/3 and leads to Actin cytoskeletal polymerization [15], [17], [18]. In addition, Rac1 modulates cytoskeleton remodeling by activating ADP-ribosylation factor interacting protein 2 (POR1) and Phosphatidylinositol-4-phosphate 5-kinase, type 1 (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 establishment of the cell polarity and promotes cellular transformation [22], [23], [24].

Activated Rac1 in turn can activate MCF.2 cell line derived transforming sequence-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 the Rac1 [26], [27].

References:

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