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, , , , . Main transcriptional activators of Rac2 promoter are Sp1 and Sp3 transcriptionfactors ( SP1 and SP3 ) . Activation of Rac proteins ismediated by guanine nucleotide exchange factors (GEFs), main GEFs for Rac2 areT-cell lymphoma invasion and metastasis 1 ( TIAM1 ) ,Phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1 ( PREX1 ),  and Vav 1 guanine nucleotide exchange factor (VAV-1 )  which is most efficient in inducing oxidase activity ofRac2 . Rac2 is isoprenylated at its C-terminus by Geranylgeranyltransferase type I (GGTase-I ), such modification may influence on Rac2 membrane transport fromcytosol , . Rac2 activity is inhibited by GTPase-activating proteins (GAPs), known GAPs forRac2 are Breakpoint cluster region ( BCR ), Active BCR-related gene (ABR ) ,  and Rac GTPase activating protein 1 (RacGAP1 ) , . 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) ) . Also, Rac2 stimulates Nitric oxide ( NO ) production byinteracting with Nitric oxide synthase 2A ( iNos ) , . In addition, Rac2 promotes Phospholipase C, beta 2 ( PLC-beta 2) activation and 1,2-diacyl-glycerol ( DAG ) production . Important effector of Rac2 is p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1 ). Activated by Rac2, it stimulates activity of NADPH oxidasesubunits . 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 ) . Rac2 is a criticalregulator of NADPH oxidase activity and assembly in phagocytic cells ,, . 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 , , , . Rac2 also binds toNADPH oxidase activator 1 ( NOXA1 ) which stimulates activity of p47-phox. 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 , .