Disease relevance of RAC2

• Repression of rac2 mRNA expression by Anaplasma phagocytophila is essential to the inhibition of superoxide production and bacterial proliferation [1].
• Epstein-Barr virus (EBV) transformed B lymphocytes, which express rac1 and rac2 genes, also efficiently release superoxide anions when triggered by various cell surface stimuli [2].
• In this study we have quantitated Rac1 and Rac2 in human neutrophils and show that > 96% of the Rac protein is Rac2 and that chronic granulomatous disease (CGD) neutrophils contain normal levels of the protein [3].
• Thus, the involvement of small G proteins in hypertrophy has become an area of significant interest [4].
• Little is known about the expression and mutation of Rac2 in human brain tumors [5].

Psychiatry related information on RAC2

• Changes in the expression of the small G-protein p21ras, a critical regulator of cell proliferation and differentiation, were investigated by immunohistochemical methods in the temporal cortex of patients with Alzheimer's disease [6].

High impact information on RAC2

• Evidence for various stimulatory agents (two small G protein families, protein kinase C, and phosphoinositides) suggests complex regulatory mechanisms, and some studies suggest a role for this enzyme activity in intracellular membrane traffic [7].
• The factor was purified to homogeneity from bovine brain cytosol and identified as a member of the ADP-Ribosylation Factor (ARF) subfamily of small G proteins [8].
• Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK [9].
• Rhodopsin-family receptors associate with small G proteins to activate phospholipase D [10].
• In the case of the small G protein Arf1, the exchange of bound GDP for GTP promotes the coating of secretory vesicles in Golgi traffic [11].

Chemical compound and disease context of RAC2

• These results indicated that VPS28, a component of ESCRT-I, and Cdc42, a small G protein, are associated with the M1 protein and involved in the influenza virus life cycle [12].
• Clostridium botulinum C3 exoenzyme (C3), which is known to selectively impair the function of Ras-related small G-protein p21rho (Rho), significantly reduced the motility of SAS cells [13].
• The domains were derived from Clostridium difficile B-toxin and Clostridium sordelli lethal toxin, which glycosylate small G-proteins, and from Clostridium botulinum C2 toxin, which ADP-ribosylates actin [14].
• Pretreatment of cells with pertussis toxin results in defective activation of Rac2 in response to fMLP and LTB4, indicating that coupling of the receptors to Gi plays a crucial role in the activation [15].
• Decreased expression of a member of the Rho GTPase family, Cdc42Hs, in cells from Tangier disease - the small G protein may play a role in cholesterol efflux [16].

Biological context of RAC2

• The RAC1 but not RAC2 gene contains an additional exon 3b that is included by alternative splicing into the variant Rac1b, a constitutively active mutant which induces the formation of lamellipodia in fibroblasts [17].
• The small GTP-binding proteins Rac1 and Rac2 are critically important in regulating multiple signal transduction pathways in eukaryotic cells [18].
• These results suggest that 1) the membrane cytoskeleton participates in respiratory burst oxidase activation, 2) the fully phosphorylated p47phox is located in the active oxidase, which resides in the membrane cytoskeleton, and 3) Rac2 acts like a dedicated component of the respiratory burst oxidase [19].
• The partial amino acid sequence of SOCI thus far determined was identical to the amino acid sequence deduced from the cDNA encoding rac2 p21 [20].
• The fact that only Rac1 but not Rac2 (the dominating Rac) redistributed to the detergent-insoluble fraction and that it was independent of GTP loading excludes the possibility that down-regulation of Rac activities was due to depletion of GTP-bound Rac from the detergent-soluble fraction [21].

Anatomical context of RAC2

• RAC2 GTPase deficiency and myeloid cell dysfunction in human and mouse [22].
• Regulation of mitogen-activated protein kinases in cardiac myocytes through the small G protein Rac1 [23].
• We report here that the stimulation of the low-affinity receptor for immunoglobulin G (IgG) (FcgammaRIIIA, CD16) on primary human natural killer (NK) cells induces a phosphatidylinositol 3-kinase (PI3K)-dependent activation of the small G protein Arf6 [24].
• We used a cell-free translocation system as well as intact normal and CGD neutrophils to determine whether the translocation of Rac2 is dependent upon the presence of the other oxidase components [3].
• Rac2 protein expression was absent in infected HL-60 cells [1].

Associations of RAC2 with chemical compounds

• The guanosine 5'-(3-O-thio)triphosphate-bound form, but not the GDP-bound form, of this small G protein showed the SOCI activity [20].
• In human neutrophils, beta2 integrin engagement mediated a decrease in GTP-bound Rac1 and Rac2 [21].
• Quantitative RT-PCR demonstrated that rac2 mRNA expression was reduced 7-fold in retinoic acid-differentiated HL-60 cells and 50-fold in neutrophils following A. phagocytophila infection [1].
• The component was isolated as a complex of rho-GDP dissociation inhibitor (rho-GDI) and two members of the rho subfamily of ras-related guanine nucleotide binding proteins, rac2 and CDC42Hs [25].
• Arf family small G-proteins act at multiple sites as regulators of membrane trafficking and actin cytoskeletal remodelling, and regulate a feedback loop comprising phospholipase D, phosphatidic acid, PIPKs and PtdIns(4,5)P2, contributing to enhancement of PtdIns(4,5)P2-mediated cellular events and receptor signalling [26].

Physical interactions of RAC2

• Finally, we observe that p67phox interacts 6-fold better with Rac2 than with Rac1 [27].
• The Rac target NADPH oxidase p67phox interacts preferentially with Rac2 rather than Rac1 [27].
• Native prenylated small G proteins are either in the form of a complex in which the GDP bound G protein is associated with a guanine nucleotide dissociation inhibitor, GDI, or in an active GTP bound form able to trigger the activity of its effector [28].
• We have solved the crystal structure of a complex between the RhoGDI homolog LyGDI and GDP-bound Rac2, which are abundant in leukocytes, representing the cytosolic, resting pool of Rho species to be activated by extracellular signals [29].
• Both these p120Ras-GAP-binding proteins are of interest in connection with the regulation of the respiratory burst oxidase, Rap1A/Krev1 because it copurifies with cytochrome b558 and p190Ras-GAP because it inhibits the Rac2-dependent activation of the respiratory burst oxidase in a cell-free system [30].

Regulatory relationships of RAC2

• In contrast, Rac2 displays a slower nucleotide association and is more efficiently activated by the Rac-GEF Tiam1 [31].
• Rac1 and Rac2 are interchangeable in their abilities to activate NADPH oxidase [1].
• PAK2 is activated by autophosphorylation upon binding of small G proteins such as Cdc42 and Rac in the GTP-bound state [32].
• IRSp53 also binds to the activated form of the small G-protein cdc42 [33].
• This PLD-stimulating activity seemed to be attributed to a small G protein RhoA [34].

Other interactions of RAC2

• We examined the activation of Rho family small G proteins and the regulation of MAPKs through Rac1 in cardiac myocytes [23].
• However, Rac2 was not transferred to the membrane during activation of p47phox-deficient neutrophils [19].
• In normal cells, some p47phox also became associated with the non-cytoskeletal portion of the plasma membrane, but p67phox, Rac2, and O(2-)-forming activity were restricted to the cytoskeleton [19].
• Structure and chromosomal assignment to 22q12 and 17qter of the ras-related Rac2 and Rac3 human genes [35].
• In addition, the stable expression of DOCK2 in Jurkat cells exhibited the elevated activity of endogenous Rac2 [36].

Analytical, diagnostic and therapeutic context of RAC2

• The dissociation constant (K(d)) for interaction between actin and p47(phox) was estimated to be 0.45 microM by surface plasmon resonance, and that between actin and rac1 or rac2 was 1.7 or 4.6 microM, respectively [37].
• In the present studies, oligonucleotide-directed mutagenesis was used to introduce a series of mutations into human rap1a or rac2 in the mammalian expression vector pSR alpha neo [38].
• Full-length posttranslationally modified Rac2 was active, whereas only the 1-166 truncated form of Rap1a was functional in the cell-free system, and thus, clarification of the function of Rap1a and Rac2 in intact human phagocytes is needed to provide further insight into their roles as signal transducers from plasma membrane receptors [38].
• Western blot analysis of lysates from patient neutrophils demonstrated decreased levels of Rac2 protein [39].
• Gel permeation chromatography of radiolabeled hydrocarbons released from the rac1, rac2, and ralA proteins by reaction with Raney nickel catalyst indicated that unlike p21Hras, which was modified by a 15-carbon moiety, the rac and ralA translation products were modified by 20-carbon isoprenyl groups [40].

References