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G-protein signaling Rac2 regulation pathway


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G-protein signaling Rac2 regulation pathway

Rac2 regulation pathway

Ras-related C3 botulinum toxin substrate 2 ( Rac2 ) belongs to family of smallRho guanosine triphosphatases (GTPases) and it is a critical signaling regulator inmammalian cells. Expression of Rac2 is restricted to cells of hematopoieticorigin. It plays critical roles in a wide variety of primary hematopoietic cells,including the regulation of adhesion, migration, oxidase activity, and gene expression[1], [2], [3], [4], [5].

Main transcriptional activators of Rac2 promoter are Sp1 and Sp3 transcriptionfactors ( SP1 and SP3 ) [6]. Activation of Rac proteins ismediated by guanine nucleotide exchange factors (GEFs), main GEFs for Rac2 areT-cell lymphoma invasion and metastasis 1 ( TIAM1 ) [7],Phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1 ( PREX1 )[8], [9] and Vav 1 guanine nucleotide exchange factor (VAV-1 ) [10] which is most efficient in inducing oxidase activity ofRac2 [5].

Rac2 is isoprenylated at its C-terminus by Geranylgeranyltransferase type I (GGTase-I ), such modification may influence on Rac2 membrane transport fromcytosol [11], [12].

Rac2 activity is inhibited by GTPase-activating proteins (GAPs), known GAPs forRac2 are Breakpoint cluster region ( BCR ), Active BCR-related gene (ABR ) [13], [14] and Rac GTPase activating protein 1 (RacGAP1 ) [15], [16].

Activated Rac2 interacts with several effectors which promote activation ofimportant cellular pathways. It was shown that Rac2 can bind and activatePhosphoinositide-3-kinase, regulatory subunit 1 ( PI3K reg class IA (p85) ) [17]. Also, Rac2 stimulates Nitric oxide ( NO ) production byinteracting with Nitric oxide synthase 2A ( iNos ) [18], [19]. In addition, Rac2 promotes Phospholipase C, beta 2 ( PLC-beta 2) activation and 1,2-diacyl-glycerol ( DAG ) production [20].

Important effector of Rac2 is p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1 ). Activated by Rac2, it stimulates activity of NADPH oxidasesubunits [21].

NADPH oxidase is a multisubunit complex. It comprises of the Cytochrome b-558,which is a heterodimer composed of a large Cytochrome b-245, beta polypeptide (gp91-phox ) and a small Cytochrome b-245, alpha polypeptide ( p22-phox )subunit. Oxidase activation is controlled by the recruitment of cytosolic regulatoryproteins to the Cytochrome b-558, including the Neutrophil cytosolic factors 1and 2 ( p47-phox and p67-phox ) [5]. Rac2 is a criticalregulator of NADPH oxidase activity and assembly in phagocytic cells [22],[23], [24]. Ezrin ( VIL2(ezrin) ) and Radixin ( RDX(radixin) ) bind to Rho GDP dissociation inhibitor (GDI) alpha ( RhoGDIalpha ) and remove it from binding with Rac2 in cytosol thus promotingRac2 binding to p67-phox and translocation to plasma membrane [25], [26], [27], [28]. Rac2 also binds toNADPH oxidase activator 1 ( NOXA1 ) which stimulates activity of p47-phox[29]. p47-phox and p67-phox bind to Cytochrome b-558subunits and thus promote NADPH oxidase activation, Superoxide anion ( O(2)(-) )production and initiation of oxidative stress [30], [28].