Disease relevance of RAC1

• The neutrophil NADPH oxidase activation factors, p47, p67 and the small guanosine-nucleotide-binding regulatory (G) protein Rac1, were expressed in a baculovirus/insect cell system and purified [1].

High impact information on RAC1

• Synthesis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], a signaling phospholipid, is primarily carried out by phosphatidylinositol 4-phosphate 5-kinase [PI(4)P5K], which has been reported to be regulated by RhoA and Rac1 [2].
• Activation of Rac1 by shear stress in endothelial cells mediates both cytoskeletal reorganization and effects on gene expression [3].
• Fluorescence resonance energy transfer (FRET) localizes activated Rac1 in the direction of flow [3].
• This directional Rac1 activation is downstream of shear-induced new integrin binding to extracellular matrix [3].
• Additionally, Rac1 mediates flow-induced stimulation of nuclear factor kappaB (NF-kappaB) and the subsequent expression of intercellular cell adhesion molecule 1 (ICAM-1), an adhesion receptor involved in the recruitment of leukocytes to atherosclerotic plaque [3].

Biological context of RAC1

• We examined the importance of the Rho family GTPase Rac1 for cyclin D(1) promoter transcriptional activation in bovine tracheal myocytes [4].
• The activation of Rac1 and phosphorylation of its effector PAK were evaluated with a pull-down assay and immunoblot analysis, respectively [5].
• The effects of mutant forms of Rac1 were determined by cell transfection [5].
• Finally, like Rac1, active Cdc42 induced transactivation of the cyclin D1 promoter cAMP response element binding protein/activating transcription factor-2 binding site [6].
• Transfection with an activated mutant of Rac1 induced lamellipodia in all directions and attenuated the shear-induced migration, suggesting that an appropriate level of Rac activity and a polarized lamellipodial protrusion are important for cell migration under static and shear conditions [7].

Anatomical context of RAC1

• In bovine adrenal chromaffin cells, we found Rac1, but not Cdc42, to be rapidly and selectively activated by secretory stimuli using an assay selective for the activated GTPases [8].
• These findings suggest that Rac1, in part, functions to modulate secretion through actions on the cytoskeleton [8].
• Taken together, these data suggest a model by which two distinct signaling pathways, the ERK and Rac1 pathways, positively regulate cyclin D(1) and smooth muscle growth [4].
• We showed that it mediates cytoskeletal reorganizations in bovine aortic endothelial (BAE) and Chinese hamster ovary (CHO) cells and does so by acting upstream of Rac1 activation [9].
• Role of rac1 in fibronectin-induced adhesion and motility of human corneal epithelial cells [5].

Associations of RAC1 with chemical compounds

• Likewise, overexpression of vRAC, a constitutively active RAC1, increased caspase-3 activity to the same extent as palmitate alone [10].
• Overexpression of an N-terminal fragment of p67(phox), a component of NADPH oxidase which interacts with Rac1, attenuated PDGF-induced cyclin D(1) promoter activity, whereas overexpression of the wild-type p67 did not [4].
• Pretreatment with ebselen, catalase, and the flavoprotein inhibitor diphenylene iodonium each attenuated PDGF- and Rac1-mediated cyclin D(1) promoter activation, while having no effect on the induction of cyclin D(1) by mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase-1 (MEK1), the upstream activator of ERKs [4].
• Rac1 forms part of the NADPH oxidase complex that generates reactive oxygen species such as H(2)O(2) [4].
• By confocal immunofluorescence analysis, we found that Rac1 and Cdc42 are exclusively localized in the subplasmalemmal region in both resting and nicotine-stimulated cells [11].

Regulatory relationships of RAC1

• We exploited the p21-activated kinase pulldown assay to identify proteins associated with activated Rac1 and found that epinephrine stimulated the association of eNOS with Rac1; epinephrine-stimulated eNOS-Rac1 interactions were blocked by the beta(3)AR antagonist SR59230A [12].

References