Disease relevance of Rac2

• Rac2-deficient mice displayed peripheral blood B lymphocytosis and marked reductions in peritoneal cavity B-1a lymphocytes, marginal zone B lymphocytes, and IgM-secreting plasma cells as well as reduced concentrations of serum IgM and IgA [1].
• We recently described an immunodeficient patient with severe, recurrent bacterial infections that had a point mutation in one allele of the Rac2 gene, resulting in the substitution of aspartate 57 with asparagine [2].
• Rac2-deficient mice and a human patient with a D57N Rac2 mutant share a phenotype of leukocytosis with defective neutrophil chemotaxis and superoxide production in response to some, but not all, agonists [3].

High impact information on Rac2

• We used a complementary DNA subtraction method, representational display analysis, to show that the small guanosine triphosphatase Rac2 is expressed selectively in murine TH1 cells [4].
• Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation [4].
• Recent studies of leukocytes derived from Rac1- and Rac2-knockout mice have shown that these highly homologous GTPases have unique biological roles [5].
• These results suggest that Rac2 plays a unique role in multiple cellular functions and describe an essential role for Rac2 in growth factor-dependent survival and expression of BAD/Bcl-XL [6].
• Mast cells generated from Rac2-deficient (-/-) mice demonstrated defective actin-based functions, including adhesion, migration, and degranulation [6].

Biological context of Rac2

• Thus, these studies identify Rac2 as a novel mediator of cross-talk between PI-3K and the p21(ras)-ERK pathway which functions to alter the cellular phenotype of a cell lineage involved in the pathologic complications of a common genetic disease [7].
• Constitutively active Rac2, GFP-Rac2(Q61L), was predominantly localized at the endomembranes; these endomembranes fused to the phagosome through the linear structure during phagocytosis, and this accumulation mechanism did not depend on positive charge in the PB region [8].
• Localization of Rac2 via the C terminus and aspartic acid 150 specifies superoxide generation, actin polarity and chemotaxis in neutrophils [9].
• Rac2, a hematopoiesis-specific Rho GTPase, specifically regulates mast cell protease gene expression in bone marrow-derived mast cells [10].
• Our data demonstrate remarkable specificity in the regulation of gene expression by Rac2 versus Rac1 [10].

Anatomical context of Rac2

• Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro [7].
• By contrast, Rac2 null neutrophils can orient toward the chemoattractant source but are unable to migrate efficiently [11].
• In contrast, mouse embryo fibroblasts derived from the Rac2 knockout mice utilize Rac1 for migration via alphavbeta3/alphavbeta5 and alpha4beta1 [12].
• Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles [13].
• These results provide genetic evidence that although Rac2 is a relatively minor isoform in murine macrophages, it plays a nonoverlapping role with Rac1 to regulate host defense functions in this phagocyte lineage [13].

Associations of Rac2 with chemical compounds

• Rac2 specificity in macrophage integrin signaling: potential role for Syk kinase [12].
• P-Rex1 is a primary Rac2 guanine nucleotide exchange factor in mouse neutrophils [14].
• The PB region of Rac1 showed strong phospholipid interaction with PI(3)P, PI(4)P, PI(5)P, PI(3,4,5)P3, and phosphatidic acid, however, that of Rac2 did not [8].
• Despite having a high degree of sequence similarity, the Rho guanosine triphosphatases Rac1 and Rac2 regulate distinct functions in neutrophils [9].
• We have shown previously that migration and superoxide (O2*-) production, as well as some kinase signaling pathways are compromised in mice deficient in the Ras-related Rho GTPase Rac2 [15].

Physical interactions of Rac2

• Specific ablation of the Sp1/Sp3 binding site significantly decreased Rac2 promoter activity in both RAW 264.7 and NIH-3T3 cells [16].

Enzymatic interactions of Rac2

• Rac1 and Rac2 are essential for the control of oxidative burst catalyzed by NADPH oxidase [17].

Regulatory relationships of Rac2

• However, phosphorylation of p38 mitogen-activated protein (MAP) kinase in Rac2(-/-) neutrophils was evident in response to CB/fMLP and/or TNF [18].
• Furthermore, Mig was unable to inhibit eotaxin-induced responses in Rac2-deficient eosinophils [19].

Other interactions of Rac2

• Furthermore, we link hyperactivation of the Ras-class IA-PI3K-Rac2 pathway to increased Nf1+/- mast cell migration [20].
• Although not required for translocation of p47phox and p67phox, Rac2 is necessary for optimal activity of the assembled oxidase complex, an effect that can be replaced by exogenous AA, which may act directly or via an exogenous AA-induced mediator [21].
• The Rac2 mutants V36A, F37A, and N39A all bind to both Pak1 and p67(phox), yet are unable to rescue superoxide production and chemotaxis when expressed in Rac2-/- PMN [15].
• Bone marrow-derived macrophages isolated from mice treated with polyIC to induce interferon lack detectable Rac1, and there is no compensatory increase in Rac2 or Cdc42 expression [22].
• Thus, we have defined specific sequences in Rac that specify subcellular localization and determine the specificity of Rac2 in neutrophil chemotaxis and superoxide generation [9].

Analytical, diagnostic and therapeutic context of Rac2

• Microarray analysis demonstrated that expression of 38 known genes was significantly altered in Rac2(-/-) mast cells after cytokine stimulation compared with those in wild-type cells [10].
• Rac2(-/-) neutrophils also failed to exhibit mobilization of the primary granule marker CD63+ during CB/fMLP stimulation as determined by confocal microscopy [18].
• Conditional gene targeting with a loxP-flanked Rac1 gene allowed Crerecombinase-induced deletion of Rac1 on a Rac2 null genetic background [23].
• Using a yeast two-hybrid assay, we identified Rac2, a Rho GTPase member, as a NOS2-interacting protein [24].

References