Pathway Map Details

G-protein signaling_Rac2 regulation pathway

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NADP('+), 1,2-diacyl-glycerol 3-phosphoinositol, (L)-Arginine (cytosol), VAV-1, p47-phox, iNOS, O(,2)('-), Cytochrome b-558, O(,2),, DAG,, RhoGDI alpha, SP1, PREX1, Inositol 1-phosphate, p22-phox, Tiam 1, Rac2, RacGAP1, p67-phox, VIL2 (ezrin), NAD(P)H,, PAK1, ABR, SP3, (L)-Citrulline cytosol, PLC-beta2, gp91-phox, RDX (radixin), NOXA1, BCR, NO, PI3K reg class IA (p85), GGTase-I


Rac2 regulation pathway

Ras-related C3 botulinum toxin substrate 2 ( Rac2 ) belongs to family of small Rho guanosine triphosphatases (GTPases) and it is a critical signaling regulator in mammalian cells. Expression of Rac2 is restricted to cells of hematopoietic origin. 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 transcription factors ( SP1 and SP3 ) [6]. Activation of Rac proteins is mediated by guanine nucleotide exchange factors (GEFs), main GEFs for Rac2 are T-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 of Rac2 [5].

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

Rac2 activity is inhibited by GTPase-activating proteins (GAPs), known GAPs for Rac2 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 of important cellular pathways. It was shown that Rac2 can bind and activate Phosphoinositide-3-kinase, regulatory subunit 1 ( PI3K reg class IA (p85) ) [17]. Also, Rac2 stimulates Nitric oxide ( NO ) production by interacting 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 oxidase subunits [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 regulatory proteins to the Cytochrome b-558, including the Neutrophil cytosolic factors 1 and 2 ( p47-phox and p67-phox ) [5]. Rac2 is a critical regulator 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 ( RhoGDI alpha ) and remove it from binding with Rac2 in cytosol thus promoting Rac2 binding to p67-phox and translocation to plasma membrane [25], [26], [27], [28]. Rac2 also binds to NADPH oxidase activator 1 ( NOXA1 ) which stimulates activity of p47-phox [29]. p47-phox and p67-phox bind to Cytochrome b-558 subunits and thus promote NADPH oxidase activation, Superoxide anion ( O(2)(-) ) production and initiation of oxidative stress [30], [28].


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