Disease relevance of RAC1

• When applied to human prostate cancer PC-3 cells, it was able to inhibit the proliferation, anchorage-independent growth and invasion phenotypes that require the endogenous Rac1 activity [1].
• In this study, we showed that c-Abl-PKCdelta-Rac1-p38 MAPK signaling is required for the conformational changes of Bak and Bax during ionizing radiation-induced apoptotic cell death in human non-small cell lung cancer cells [2].
• Surprisingly, pertussis toxin and overexpression of the free Gbetagamma-specific sequestering minigene hbetaARK1(495) also inhibit EGLT-mediated CDC42 and Rac1 activation completely [3].
• The roles of Rac1 and TIRAP in LPS activation of HIV replication is not known [4].
• To further define the relevance of activation of the Rac1/p38 MAP kinase pathway in the induction of arsenic-dependent antileukemic effects, studies were performed using bone marrows from patients with chronic myelogenous leukemia [5].
• These results suggest that Rac1 plays a major role in colorectal adenocarcinoma progression [6].

Psychiatry related information on RAC1

• The biological mechanisms underlying the mental retardation associated with mutation of the ARHGEF6 gene, a Rac1/Cdc42 exchange factor, are still unknown, although defects in the plasticity of synaptic networks have been postulated [7].

High impact information on RAC1

• The effector IpgB2 stimulates cellular responses analogous to GTP-active RhoA, whereas IpgB1 and Map function as the active forms of Rac1 and Cdc42, respectively [8].
• Indeed, expression of constitutively active forms of Rho1 or Rac1 in adult flies results in ethanol resistance similar to that observed in whir mutants [9].
• Here we describe the solution structure of the N-terminal DH domain of Trio that catalyzes nucleotide exchange for Rac1 [10].
• Taken together, these findings strongly support a critical role for Rac1 and Cdc42 in controlling the JNK signaling pathway [11].
• Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck [12].

Chemical compound and disease context of RAC1

• Caki-1 cells were exposed to hypoxia (1% O2) and exhibited increased Cdc42, Rac1 and RhoA protein expression [13].
• Expression of active Rac1 induced an internalization of E. coli that was insensitive to wortmannin and genistein [14].
• Internalization of type 1-piliated E. coli (fimH+) and FimH-coated micro-spheres was inhibited by compactin, a pan-Rho-GTPase inhibitor and dominant negative isoforms of Rac1 and Cdc42 [14].
• Rac1-NADPH oxidase-regulated generation of reactive oxygen species mediates glutamate-induced apoptosis in SH-SY5Y human neuroblastoma cells [15].
• Phosphatidylinositol 3-kinase, Cdc42, and Rac1 act downstream of Ras in integrin-dependent neurite outgrowth in N1E-115 neuroblastoma cells [16].

Biological context of RAC1

• We recently demonstrated that the RAC1/JNK pathway is regulated by serine phosphorylation at the juxtamembrane region of RET in a cAMP-dependent manner [17].
• Southern hybridization with SbCDC42 and SbRAC1 cDNAs indicated that the S. bovinus genome contains only one CDC42 and one RAC1 gene [18].
• 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 is overexpressed in a subgroup of colorectal tumours [19].
• Inhibition of NADPH oxidase activity by DPI, apocynin, or NAC significantly decreased TLR4 mRNA stability, as did the knock-down of RAC1 gene expression by RNA interference [20].
• At the leading edge, Rac1 and Cdc42 promote cell motility through the formation of lamellipodia and filopodia, respectively [21].

Anatomical context of RAC1

• EGF redistributes beta2-chimaerin to promote its association with the small GTPase Rac1 at the plasma membrane, as determined by FRET [22].
• We identified three proteins in neutrophil cytosol of molecular size 65, 62 and 68 kDa which interact in a GTP-dependent manner with rac1 and CDC42Hs, but not with rho [23].
• The interaction with beta-Pix is nucleotide independent and is necessary and sufficient for Rac1 recruitment to membrane ruffles and to focal adhesions [24].
• DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines [25].
• We examined the activation of Rho family small G proteins and the regulation of MAPKs through Rac1 in cardiac myocytes [26].

Associations of RAC1 with chemical compounds

• This relocalization and association with Rac1 were impaired by disruption of the beta2-chimaerin C1 domain as well as by PLCgamma1 RNAi, thus defining beta2-chimaerin as a novel DAG effector [22].
• The chemical compound NSC23766 was identified by a structure-based virtual screening of compounds that fit into a surface groove of Rac1 known to be critical for GEF specification [1].
• We also found that CrkL-induced activation of small guanine triphosphatase (GTPase) Rac1 was significantly inhibited by the DOCK2-dCS mutant in 293T cells [25].
• In human neutrophils, beta2 integrin engagement mediated a decrease in GTP-bound Rac1 and Rac2 [27].
• Phosphoinositide 3-kinase also bound to Rac1 and Cdc42Hs, and these interactions were GTP-dependent [28].
• We propose a novel mechanism in which alpha6beta4 integrin signaling via Rac1, 14-3-3 proteins, and SSH family members regulates cofilin activation, cell polarity, and matrix assembly, leading to specific epidermal cell migration behavior [29].

Physical interactions of RAC1

• Rac1 interacted directly with p67phox in a GTP-dependent manner [30].
• Here we have characterized the interaction of Rac1 with a panel of mammalian GAPs and putative effectors by measuring the kinetic and binding parameters involved and made comparisons with similar interactions for Cdc42 and RhoA [31].
• TPR domain mutants of NOXA1 that interfere with Rac1 binding were ineffective in supporting Nox1-dependent ROS generation [32].
• The formation of E-lams was dependent on fibronectin-binding integrins and normally regulated Rac1, and expression of either dominant-negative or constitutively active forms of Rac1 prevented E-lam formation [33].
• CYFIP1/2 are proteins of unknown function, but CYFIP1 has recently been shown to interact with the small GTPase Rac1, which is implicated in development and maintenance of neuronal structures [34].

Enzymatic interactions of RAC1

• The Rac1-specific guanine nucleotide exchange factor Vav is heavily phosphorylated on tyrosine residues upon CD5 costimulation, which is a prerequisite for its activation [35].
• We demonstrated that FAK tyrosine-phosphorylated betaPIX and thereby increased its binding to Rac1 [36].

Co-localisations of RAC1

• Endogenous Rac1 colocalized with ARF6 at the plasma membrane and on the ARF6 recycling endosome in untransfected HeLa and primary human fibroblast cells [37].
• AIF-1 colocalizes with Rac1, and AIF-1-transduced VSMCs show a constitutive and enhanced activation of Rac1, providing a mechanism for the increased migration [38].

Regulatory relationships of RAC1

• RhoG is a member of the Rho family of GTPases that activates Rac1 and Cdc42 through a microtubule-dependent pathway [39].
• Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA [31].
• Nox1-dependent reactive oxygen generation is regulated by Rac1 [32].
• The binding of HA to keratinocytes promotes PKNgamma kinase recruitment into a complex with CD44 and subsequently stimulates Rac1-mediated PKNgamma kinase activity [40].
• Herceptin blocked basal and TGF-beta-stimulated Rac1 activity but did not repress TGF-beta-stimulated transcriptional reporter activity [41].
• Rac1 was activated in infected cells and accumulated with F-actin in a PI3K-independent manner at bacterial entry sites [42].

Other interactions of RAC1

• The Rho family of small GTPases (RhoA, Rac1 and Cdc42) controls signal-transduction pathways that influence many aspects of cell behaviour, including cytoskeletal dynamics [21].
• These results constitute the first report of a Syk --> PI3K --> Rac1 --> Akt signal cascade controlled by IL-2 that mediates NK cell survival [43].
• The present studies demonstrate that Nox1, a homolog of the phagocyte NADPH-oxidase component gp91(phox), is activated by Rac1 [32].
• Rac3 differs from Rac1/2 at its carboxyl-terminal end, a domain associated with subcellular localization and binding to specific cellular regulators [44].
• A 68-kDa kinase and NADPH oxidase component p67phox are targets for Cdc42Hs and Rac1 in neutrophils [45].

Analytical, diagnostic and therapeutic context of RAC1

• In the present study, we found that alphav integrin ligation activated small GTPase Rac1 preferentially, and dominant negative Rac1 inhibited alphav integrin-mediated p38 MAPK activation [46].
• VSMC microinjection with antibodies to either Rho or Rac1 decreased uPA-stimulated cell migration, indicating the involvement of both GTPases in the migration process [47].
• Immunofluorescence experiments demonstrated clear colocalization of PKG and Rac1 in membrane ruffles and dynamic membrane regions supporting a functional interaction [48].
• The GC-rich gene promoter shows characteristics of a housekeeping gene and Northern blot studies revealed ubiquitous expression of two rac1 transcripts, 1.2 and 2.5 kb in size [49].
• 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 [50].

References