Disease relevance of Rac1

• Taken together, we believe that the linkage between CD44v3 isoform and the PHn-CC-EX domain of Tiam1 is required for HA stimulated Rac1 signaling and cytoskeleton-mediated tumor cell migration during breast cancer progression [1].
• RESULTS AND CONCLUSIONS: Rac1 and Cdc42 activities are required for maximal activity of the collagen X promoter, a hypertrophic marker, in primary chondrocytes, suggesting essential roles of these GTPases in chondrocyte hypertrophy [2].
• Furthermore, experiments using a dominant-negative form demonstrate that STEF/Tiam1 mediate extracellular laminin signals to activate Rac1, promoting neurite growth in N1E-115 neuroblastoma cells [3].
• This study verifies the role of Rac1 during light-induced retinal degeneration [4].
• HGF remarkably stimulated cell motility and scattering of synovial sarcoma cell lines, consistent with the prominent activation of Rac1, extreme filopodia formation, and membrane ruffling [5].

High impact information on Rac1

• YpkA inhibits nucleotide exchange in Rac1 and RhoA, and mutations that disrupt the YpkA-GTPase interface abolish this activity in vitro and impair in vivo YpkA-induced cytoskeletal disruption [6].
• Here we solve the crystal structure of a YpkA-Rac1 complex and find that YpkA possesses a Rac1 binding domain that mimics host guanidine nucleotide dissociation inhibitors (GDIs) of the Rho GTPases [6].
• Activation requires an intact effector domain and isoprenylation of Cdc42 and Rac1 [7].
• Here we investigate the role of Rac1 in cell transformation and show that Rat1 fibroblasts expressing activated Val-12 Rac1 (Rac1 with valine at residue 12) display all the hallmarks of malignant transformation [8].
• In a focus-forming assay in NIH3T3 fibroblasts to measure the efficiency of transformation, we found that dominant-negative Asn-17 Rac1 inhibited focus formation by oncogenic Ras, but not by RafCAAX, a Raf kinase targeted to the plasma membrane by virtue of the addition of a carboxyterminal localization signal from K-Ras [8].

Chemical compound and disease context of Rac1

• CD44 interaction with tiam1 promotes Rac1 signaling and hyaluronic acid-mediated breast tumor cell migration [1].
• Tiam1 (T-lymphoma invasion and metastasis 1) is one of the known guanine nucleotide (GDP/GTP) exchange factors (GEFs) for Rho GTPases (e.g., Rac1) and is expressed in breast tumor cells (e.g., SP-1 cell line) [9].
• Potential targets of therapeutic intervention include the cytoplasmic phosphatase calcineurin and small guanosine triphosphate-binding proteins, such as Rac1 and RhoA, all of which have been implicated in maladaptive hypertrophy [10].
• Proteomic analysis of Rac1 transgenic mice displaying dilated cardiomyopathy reveals an increase in creatine kinase M-chain protein abundance [11].
• We used a doxycycline inducible system to express dominant negative Rac1 (N17 Rac1) in the squamous cell carcinomas producing 6M90 cell line [12].
• Deletion of Rac1 resulted in resistance to bleomycin-induced fibrosis and inflammation [13].

Biological context of Rac1

• In addition, a Rac1/2 or Vav1/3 deficiency blocks Arp2/3 recruitment and actin polymerization at the complement-induced phagosome, indicating that these proteins regulate early steps in phagocytosis [14].
• The LIM protein Ajuba influences p130Cas localization and Rac1 activity during cell migration [15].
• Interestingly, distinct morphological phenotypes were observed; suppression of Rac1 activity caused loss of the leading process, whereas repression of JNK activity did not, suggesting the complexity of the signaling cascade [16].
• Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass [17].
• Although a body of literature has implicated the Rho family members Rac1 and Rac2 in multiple hematopoietic-cell functions, the role of Cdc42 in hematopoiesis remains unclear [18].

Anatomical context of Rac1

• The scaffold protein, linker for activation of T cells (LAT), and Rac1 (a target of Vav activity) were constitutively present in GEMs [19].
• The mechanisms through which the small GTPases Rac1 and Cdc42 regulate the formation of membrane ruffles, lamellipodia, and filopodia are currently unknown [20].
• The Tiam1 gene encodes an activator of Rac1, and similarly to constitutively activated (V12)Rac1, overexpression of Tiam1 in fibroblasts induces the formation of membrane ruffles [21].
• Mutations that render RhoA, Cdc42hs, or Rac1, either constitutively active or dominant negative abrogated binding to RhoGDI alpha and redirected expression to both PMs and internal membranes [22].
• We demonstrate here that although Rac1 null neutrophils display normal chemokinesis, they are unable to migrate toward the source of the chemoattractant [17].

Associations of Rac1 with chemical compounds

• Moreover, DGK-zeta directly interacts with Rac1 through a binding site located within its C1 domains [23].
• The monomeric G-proteins Rac1 and/or Cdc42 are required for the inhibition of voltage-dependent calcium current by bradykinin [24].
• p19Arf-p53 tumor suppressor pathway regulates cell motility by suppression of phosphoinositide 3-kinase and Rac1 GTPase activities [25].
• 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 [26].
• The formation of primitive endoderm in response to retinoic acid also could be blocked by expression of dominant negative mutants of RhoA, Cdc42, or Rac1 [27].
• Because transitional immature murine B cells maintain lower steady-state levels of plasma membrane cholesterol, we augmented their levels to that of mature B cells and found that BCR-induced Rac1 activation and Rac1-dependent membrane ruffling and cell spreading were restored [28].

Physical interactions of Rac1

• E3 or laminin-1 increase Grb2-binding and Rac1 activation [29].
• Skeletal muscle signaling pathway through the dystrophin glycoprotein complex and Rac1 [30].
• An activating mutant of Rac1 that fails to interact with Rho GDP-dissociation inhibitor stimulates membrane ruffling in mammalian cells [31].
• Signaling from G protein-coupled receptors to c-Jun kinase involves beta gamma subunits of heterotrimeric G proteins acting on a Ras and Rac1-dependent pathway [32].
• Arg66 and Arg68 within the GTPase-binding region of Rac1 were identified as preferred sites of ExoS ADP-ribosylation [33].

Co-localisations of Rac1

• In response to EGF, the sialidase redistributed rapidly to ruffling cell membranes of squamous carcinoma A431 cells and co-localized with Rac-1 [34].

Regulatory relationships of Rac1

• Our results obtained from gene-targeted primary MEFs indicate that Rac1 is essential not only for lamellipodia induction but also for the RhoA-regulated actin stress fiber and focal adhesion complex formation and that Rac1 is involved in cell survival regulation through anoikis-dependent as well as -independent mechanisms [35].
• Furthermore, these results suggest that although both Cdc42Hs and Rac1 can activate p38 in situ, the effects of Cdc42Hs and Rac1 on cell cycle progression are, in fact, quite distinct [36].
• MOCA induces membrane spreading by activating Rac1 [37].
• We report here that dominant negative forms of Rac1 and Cdc42Hs inhibit the expression of the muscle-specific genes myogenin, troponin T, and myosin heavy chain in L6 and C2 myoblasts [38].
• Cortactin redistributes from the cytoplasm into membrane ruffles as a result of growth factor-induced Rac1 activation, and this translocation is blocked by expression of dominant negative Rac1N17 [39].
• These data show a specific requirement for Rac1 function in cells expressing oncogenic K-ras [40].

Other interactions of Rac1

• Although overexpressed Cdc42hs and Rac2 were observed predominantly on endomembrane, Rac1 was predominantly at the PM [22].
• In addition, like Vav and Rac1, we found that Vav2 activated the Jun NH(2)-terminal kinase cascade and also caused the formation of lamellipodia and membrane ruffles in NIH 3T3 cells [41].
• Oncogenic activity of Tiam1 and Rac1 in NIH3T3 cells [42].
• MYC-Csl induced cell spreading and lamellipodia formation in C2C12 cells at the expense of filopodia, suggestive of modulation of Rac1 activity [43].
• Combined with PK inhibitors and genetic mutants of Rac1 and JNK in PK activity assays, Western blotting analyses, and IL-1 enzyme-linked immunosorbent assay, the role of individual PKs in the regulation of proIL-1/IL-1 was extensively dissected [44].
• We conclude that PI3K/p110alpha mediates growth factor-dependent ROS production by recruiting p47(phox) and Rac-1 to the cell membrane, thereby assembling the active Nox complex [45].

Analytical, diagnostic and therapeutic context of Rac1

• Using immunoblot analysis and the PCR, we found evidence that RhoA, Rac1, and Cdc42 all are expressed in NG108-15 cells [24].
• Rac1 is an intracellular signal transducer regulating a variety of cell functions [35].
• Luciferase assays, RT-PCR, cell proliferation, alkaline phosphatases assays, staining procedures, TUNEL assays, and caspase activity assays were performed to study the chondrocyte response to overexpression of Rac1 and Cdc42 proteins [2].
• Transaortic constriction as well as AngII increased the binding of Rho guanine nucleotide dissociation inhibitor (RhoGDIalpha) to Rac1 [46].
• We used conditional gene targeting to generate mice with specific Rac1 deficiency in the B cell lineage [47].

References