IndraLab

"Ubiquitylation of Rac1, RhoA and Cdc42 can be deregulated in cancer cell lines, a fact that could indicate a link between Rho GTPase protein ubiquitylation and cancer. xref For instance, the E3 ligase SMURF1 targets RhoA for degradation at the leading edge of migrating cells, affecting tumor cell migration. xref PIAS3 SUMOylates Rac1 stabilizing the active form of the protein following HGF stimulation and therefore promoting cell migration and invasion, suggesting a possible role in cancer progression. xref Conversely, Rac1 can be ubiquitylated by the E3 ligase HACE1, resulting in its proteasomal degradation, reducing Rac1 mediated migration. xref Ubiquitylation of RhoA has also been reported to be impaired following FBXL19 downregulation in lung cancer epithelial cells. xref FBXL19 ligase also ubiquitylates Rac1 and Rac3, with degradation impairing esophageal cancer cell EMT. xref Finally, phosphorylation of Rho GTPases has also been shown to regulate their transforming ability; for instance phosphorylation of Cdc42 by the Src tyrosine kinase modulates its interaction with Rho GDI which is necessary for cellular transformation. xref These examples from the literature demonstrate some of the great diversity of mechanisms by which cancer cells can indirectly disrupt upstream signals which lead to Rho GTPase activation."

"In addition, further analysis of in vitro ubiquitination of Rac1 with IAPs revealed that ubiquitin could also be conjugated by IAPs to other lysines in Rac1."

"XIAP can promote degradative ubiquitination of Rac1 at Lys147 [ xref ] and cdc42 at Lys166 [ xref ] and cIAP1 can induce ubiquitination of Rac1."

"The JNK-dependent activation of Rac1 ubiquitination would create a regulatory loop allowing the cell to counteract excessive activation of Rac1 GTPase."

"Indeed, ubiquitination of Rac1L61 is critically dependent on JNK activation."

"In this work we show that ECM mechanical properties impact Rac1-GTP ubiquitylation and thereby tune Rac1 level of activity in cells."

"HACE1 expression increases the ubiquitylation of Rac1, while RNAi-mediated depletion of HACE1 blocks the ubiquitylation of active Rac1 and increases levels of GTP-bound Rac1 [ xref ]."

"We measured that this mutant had an inhibitory effect on the ubiquitylation of Rac1 ( xref )."

"A recent E3 ligase identified as regulating the ubiquitylation of Rac1 and Rac2 in human tumor cells is the HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1)."

"For example it has also been shown that Cav1 regulates the ubiquitination and degradation of active Rac1 at focal adhesion sites xref ."

"XIAP can promote degradative ubiquitination of Rac1 at Lys147 [ xref ] and cdc42 at Lys166 [ xref ] and cIAP1 can induce ubiquitination of Rac1."

"In human, IAP s directly ubiquitinate Rac1 at lysine 147 resulting in its proteasomal degradation under CNF1 toxin treatment ( xref )."

"The ubiquitination of RAC1 at its major ubiquitination site K147, which is the Ub-site regulated in this study, is dependent on the activity of c-Jun N-terminal kinases (MAPK8, MAPK9, MAPK10) ( xref )."

"Activated Rac1, but not the tumorigenic variant Rac1b, is ubiquitinated on Lys 147 through a JNK-regulated process."

"Future studies will reveal the molecular mechanisms of XIAP- and c-IAP1-regulated Rac1 ubiquitination and whether Fbxl19, XIAP, or c-IAP1 catalyzes ubiquitination of Rac1 on the same lysine residue."

"(a) Rac1b appears to be more stable than Rac1L61 with regard to the ubiquitin-proteasome system, and this may be of importance for the expression and tumorigenic capacity of Rac1b; and (b) ubiquitination of activated Rac1 occurs through a JNK-activated process, which may explain the defective ubiquitination of Rac1b."

"We found that UbcH7, as well as E1 and ATP were all required for Rac1 ubiquitylation by HACE1, thereby establishing the ability of HACE1 to catalyze Rac1 ubiquitylation."

"It is conceivable that phosphorylation of Ser 385 reduces the pool of active HACE1 at the membrane where Rac1 ubiquitination by HACE1 occurs 3."

"The E3 ubiquitin ligase HACE1 is a potent tumor suppressor that controls cell proliferation and ubiquitylates the small GTPase Rac1 to target it to proteasomal degradation."

"Oxygen sensor FIH inhibits HACE1 dependent ubiquitination of Rac1 to enhance metastatic potential in breast cancer cells."

"Altogether, these data showed that Rac1 ubiquitylation by HACE1 is tuned by ECM stiffness via modulation of OPTN levels."

"Importantly, we observed that ubiquitylation of Rac1 by HACE1 depends on Rac1 activation state."

"Under hypoxic conditions, HACE1 is less hydroxylated due to the inactivation of FIH, and subsequently functions to ubiquitinate the active form of Rac1, leading to the proteasomal degradation of Rac1."

"The focal distribution of mutants in ANK 5 and 6 together with the present study suggest that this region is of critical importance in the mechanism that link HACE1 ubiquitylation of Rac1 to its control of cell proliferation."

"Importantly, we observed that ubiquitylation of Rac1 by HACE1 depends on Rac1 activation state."

"HACE1 ubiquitinates GTP-bound RAC1 and causes its degradation [ xref ]."

"The overexpression of HACE1 enhanced Rac1 polyubiquitination compared with control cells, whereas the overexpression of catalytically inactive HACE1 (C876S) showed no change in levels of Rac1 polyubiquitination (XREF_FIG) 16 Moreover, to verify that HACE1 ubiquitylation of Rac1 occurs at lysine 147 (citation), we ectopically expressed HA tagged wild-type Rac1 as well as a K147R mutant."

"GTP-bound Rac1 is ubiquitylated by Hace1 at lysine (K)-147 (ref. xref )."

"Thus, the decrease in levels of activated Rac1 in HACE1 overexpressing MCF7 cells is due to the proteosomal degradation of polyubiquitination of Rac1 at lysine 147 by HACE1."

"As a substrate of Hace1, Rho GTPase Rac1 can be ubiquitylated at lysine 147 by HACE1."

"Castillo-Lluva et al. further showed that HACE1 catalyzes polyubiquitination of Rac1 at lysine 147 following its activation by a migration stimulus, such as hepatocyte growth factor (HGF), resulting in Rac1 degradation by the proteasome."

"Ubiquitination of Rac1 at Lys147 by the E3 ligase HACE1 (a tumor suppressor) is another described post-translational modification that is required for proteasomal degradation of the GTP-bound protein."

"It is interesting to note that HACE1 ubiquitylates Rac1 on Lys147 XREF_BIBR, which is remote from the regions that are structurally sensitive to the bound nucleotide; furthermore, this residue is fully accessible in inactive Rac1 bound to RhoGDI XREF_BIBR."

"The overexpression of HACE1 enhanced Rac1 polyubiquitination compared with control cells, whereas the overexpression of catalytically inactive HACE1 (C876S) showed no change in levels of Rac1 polyubiquitination (XREF_FIG) 16 Moreover, to verify that HACE1 ubiquitylation of Rac1 occurs at lysine 147 (citation), we ectopically expressed HA tagged wild-type Rac1 as well as a K147R mutant."

"HACE1 expression increases the ubiquitylation of Rac1, when the GTPase is activated by point mutations or by the GEF-domain of Dbl."

"As previously reported, we found that wild-type HACE1 expression increased Rac1 ubiquitylation levels."

"Consistent with previous groups, we observed that HACE1 overexpression enhances polyubiquitination of wild-type Rac1 but not the K147R mutant (XREF_FIG)."

"HACE1 expression increases the ubiquitylation of Rac1, while RNAi mediated depletion of HACE1 blocks the ubiquitylation of active Rac1 and increases levels of GTP bound Rac1 [XREF_BIBR]."

"In good agreement with our findings that HACE1 (S385E) retains its catalytic activity, we also determined that HACE1 (S385E) induces the ubiquitination of recombinant Rac1 loaded with GTPgammaS in vitro."

"Thus, the reduced capacity of HACE1 (S385E) to ubiquitinate active Rac1 is not due to a reduced association with its target but might instead be explained by a modulation of its enzymatic activity."

"GTP bound Rac1 is ubiquitylated by Hace1 at lysine (K) -147."

"In accordance with our hypothesis, we found that the phospho mimetic mutant HACE1 (S385E) displays a reduced capacity to ubiquitinate Rac1 (Q61L) while the phospho resistant mutant HACE1 (S385A) induces Rac1 (Q61L) ubiquitination as efficiently as HACE1 (WT)."

"XIAP and c-IAP1 modulate Rac1 ubiquitination and degradation by the proteasome."

"XIAP can promote degradative ubiquitination of Rac1 at Lys147 [80] and cdc42 at Lys166 [78] and cIAP1 can induce ubiquitination of Rac1."

"UbiNet 2.0"

"XIAP can promote degradative ubiquitination of Rac1 at Lys147 [ xref ] and cdc42 at Lys166 [ xref ] and cIAP1 can induce ubiquitination of Rac1."

"Several E3 ligase, including HACE1, XIAP, c-IAP1 ubiquitinates Rac1 on Lysine residue 147, whereas FBXL19 ubiquitinates Lysine 166 [ xref , xref , xref ]."

"E3 ligases HACE1, XIAP, and SCF/FBX19 ubiquitylate Rac1, resulting in its degradation and suppressing lamellipodial protrusions."

"XIAP and c-IAP1 modulate Rac1 ubiquitination and degradation by the proteasome."

"XIAP can promote degradative ubiquitination of Rac1 at Lys147 [ xref ] and cdc42 at Lys166 [ xref ] and cIAP1 can induce ubiquitination of Rac1."

"XIAP can promote degradative ubiquitination of Rac1 at Lys147 [80] and cdc42 at Lys166 [78] and cIAP1 can induce ubiquitination of Rac1."

"XREF_BIBR While Smurf1 and Cullins (Cul3) were shown to regulate the polyubiquitination and degradation of RhoA, the E3 ligases driving Rac1 polyubiquitination were not known."

"For example, K197 is equivalent to K166 in Rac1, which is polyubiquitinated by an SCF family E3 ligase [29]."

"The E3 Ubiquitin-Ligase HACE1 907 Catalyzes the Ubiquitylation of Active Rac1."

"It has been well documented that Rac1 is ubiquitylated by E3 proteins HACE, XIAP, and c-IAP1 on K147, and by FBXL19 on K166 dependent on S71 phosphorylation [ xref , xref , xref ]."

"Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1."

"In addition, the Rac1 inhibitor (NSC23766) diminished the ubiquitination of Rac1 by coexpressed TRAF6 ( xref )."

"These data indicate that the tight interaction of TRAF6 and inactive Rac1 is likely due to inefficient ubiquitination of inactive Rac1 by TRAF6."

"Unlike its regulation of RhoA, the ubiquitination of Rac1 by SCF FBXL19 is accompanied by the phosphorylation of Rac1 by AKT."

"UbiNet 2.0"

"XREF_BIBR FBXL19 ligase also ubiquitylates Rac1 and Rac3, with degradation impairing esophageal cancer cell EMT."

"Interestingly, Rac1b ubiquitination could be stimulated by coexpression of Rac1L61, suggesting positive regulation of Rac1 ubiquitination by Rac1 downstream signaling."

"Activation of Rac1 by cytotoxic necrotizing factor 1 (CNF1) from Escherichia coli induces Rac1 poly- and mono-ubiquitination, the biological function of the latter remains unclear XREF_BIBR."

"We have previously shown in C elegans that RAC1 is ubiquitylated by PARKIN [ xref ], mutated in the juvenile variant of PD."

"We have previously shown in C elegans that RAC1 is ubiquitylated by PARKIN [XREF_BIBR], mutated in the juvenile variant of PD."

"For example, K197 is equivalent to K166 in Rac1, which is polyubiquitinated by an SCF family E3 ligase [29]."

"Induced ubiquitination of Rac1 by SCF FBXL19 leads to a reduction in Rac1 levels and decreased cell motility."

"For instance, inhibitors of HACE1 or HUWE1 significantly decreased ubiquitination of the HACE1 target Rac1 (XREF_SUPPLEMENTARY) or stabilized the protein levels of HUWE1 and its substrate c-Myc, respectively (XREF_SUPPLEMENTARY)."

"For instance, inhibitors of HACE1 or HUWE1 significantly decreased ubiquitination of the HACE1 target Rac1 or stabilized the protein levels of HUWE1 and its substrate c-Myc, respectively."

"Interestingly, Rac1b ubiquitination could be stimulated by coexpression of Rac1L61, suggesting positive regulation of Rac1 ubiquitination by Rac1 downstream signaling."

"We showed that HACE1 knockdown exacerbated LPS-induced neuroinflammation in BV2 microglial cells in vitro through suppressing ubiquitination and degradation of activated Rac1, an NADPH oxidase subunit."

"Instead, we found that the adenosine triphosphatase function of Rlip76 modulates Rac1 activity by regulating Rac1 protein ubiquitylation and degradation."

"We further demonstrated that the decrease of Rac1 after ZER treatment is via proteasome dependent degradation pathway, and ZER treatment drastically enhanced ubiquitination of Rac1, which finally caused Rac1 degradation."

"We found that Smurf1, a HECT domain E3 ubiquitin ligase, could specifically target RhoA but not Cdc42 or Rac1 for degradation"

"Interestingly, Rac1b ubiquitination could be stimulated by coexpression of Rac1L61, suggesting positive regulation of Rac1 ubiquitination by Rac1 downstream signaling."

"In addition, the Rac1 inhibitor (NSC23766) diminished the ubiquitination of Rac1 by coexpressed TRAF6 (XREF_SUPPLEMENTARY)."

"Instead, we found that the adenosine triphosphatase function of Rlip76 modulates Rac1 activity by regulating Rac1 protein ubiquitylation and degradation."

"In conclusion, OPTN positively controls the ubiquitylation of Rac1 by HACE1 E3 ubiquitin ligase, thereby limiting Rac1 activity in cells."

"In addition, the Rac1 inhibitor (NSC23766) diminished the ubiquitination of Rac1 by coexpressed TRAF6 (XREF_SUPPLEMENTARY)."

"Furthermore, the addition of NKD1 to Rac1 transfected cells increased Rac1 polyubiquitination (XREF_FIG and XREF_SUPPLEMENTARY)."

"The JNK dependent activation of Rac1 ubiquitination would create a regulatory loop allowing the cell to counteract excessive activation of Rac1 GTPase."

"Immunoprecipitation and Western blot analysis confirmed that the transduced TAT-HACE1 [identified by its hemagglutinin (HA) tag] can immunoprecipitate Rac1 and ubiquitinate Rac1, and that Rac1 can imm[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"Group-I PAKs mediated phosphorylation of HACE1 at serine 385 regulates its oligomerization state and Rac1 ubiquitination."

"We found that caveolin-1 mediates Rac1 poly-ubiquitylation and degradation and that PACSIN2 targets Rac1 to an endocytic pathway involving GAP proteins."

"Anti-RAC1 immunoprecipitated material from total cell lysates contained HACE1, in addition to RAC1 and polyubiquitinated RAC1 proteins."

"Taken together, our data suggest that AhR activation by BaP induces JNK dependent RAC1 ubiquitination, which inhibits the RAC1-PI3K-AKT-signaling axis after TLR4 activation and thus potentially contributes to the AhR dependent attenuation of pro inflammatory signaling in a non genomic manner (XREF_FIG)."