IndraLab
Statements
sparser
"Notably, the Catalogues of Somatic Mutations in Cancer (COSMIC v96, Sanger Institute) lists Arg332 at the WT HACE1–RAC1 interface as the most reported mis‐sense substitution site linked to cancer in HACE1 (Table xref , Supporting Information). [ xref ] Our in vitro ubiquitination assay showed that mutation at Arg332 in the MID domain increased RAC1 ubiquitination (Figure xref )."
sparser
"This feature of RAC1B may be of importance for the expression and tumorigenic capacity of RAC1B. Mutational analysis of all lysine residues in RAC1 revealed that the major target site for RAC1 ubiquitination is Lys147, a solvent-accessible residue that has a similar conformation in RAC1B. Like RAC1-Q61L, RAC1B was found to be largely associated with the plasma membrane, a known prerequisite for RAC1 ubiquitination."
sparser
"Atorvastatin inhibited inflammatory cytokine secretion by facilitating proteasome degradation of RAC1 [ xref ], and MG53 could catalyze RAC1 ubiquitination modification [ xref ]; Skp1-Cul1-F-box (SCF) FBXL19 mediated RHOA ubiquitination and proteasomal degradation in lung epithelial cells [ xref ]; X-linked inhibitor of apoptosis protein bound to CDC42 targeting it for proteasomal degradation [ xref ]."
sparser
"Acosta et. al. showed that HACE1 phosphorylation at S385 by group I PAKs in vivo results in greater homo‐oligomerization but less ubiquitination of RAC1. [ xref ] This S385 residue is adjacent to the insertional loop (aa 386–441) of the MID domain, which we were unable to model."
sparser
"Additionally, the previous study showed that the phospho‐mimetic HACE1 (S385E) mutant (greater oligomerization) had a reduced capacity to facilitate ubiquitination of active RAC1, and surmised that this site was therefore more likely to be linked to modulation of HACE1 enzymatic activity rather than target protein association. [ xref ] We speculate that higher oligomer of HACE1 is energetically unfavorable in vitro but can be stabilized by posttranslational modification in vivo as a part of regulatory mechanism."
sparser
"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 )."
sparser
"In line with HACE1’s role in Rac1 ubiquitination, increased levels of the active form of Rac1 were observed in knockout models and patient-derived fibroblasts with loss of HACE1 expression, which indeed showed a much faster migration in comparison to wildtype [ xref , xref , xref ]."
| PMC
sparser
"Although these molecules may inhibit cell migration under certain conditions, potentially via ubiquitination of Rac1 [ xref ], or regulation of RAF destruction [ xref ], most data suggest that IAPs [ xref , xref ] function as potentially evolutionary-conserved [ xref ] enablers of cell motility [ xref ]."
sparser
"Reduction in Cav1 expression results in the accumulation of non‐ubiquitylated and mono‐ubiquitylated Rac1, but does not affect the level of poly‐ubiquitylated Rac1, suggesting that Cav1 plays a specific role in the regulation of polyubiquitylation and subsequent degradation of Rac1. xref Felley‐Bosco et al xref reported that Cav1 is involved in the degradation of inducible nitric oxide synthase in the cytosol, but the molecular mechanism remains unclear."
sparser
"For example, in mouse lung epithelial cells, FBXL19 regulates cell proliferation by mediating the stability of RhoA [ xref ], inhibits cell migration by promoting the ubiquitination and degradation of Rac1 [ xref , xref ], and attenuates IL-33-induced apoptosis by mediating the ubiquitination degradation of ST2L [ xref ]."
sparser
"A two-hybrid screen in yeast for ub-Rac1 chimera interacting proteins allowed us to isolate Tollip (Toll and IL1-Receptor interacting protein). xref Tollip comprises an ubiquitin binding domain and a TBD-domain for interaction with the clathrin-interacting protein Tom1. xref Tollip, Tom1 and clathrin localize at the site of internalized bacteria. xref These factors are required for efficient bacterial entry into cells intoxicated by CNF1, or expressing active Rac1, via a β-1 integrin pathway. xref Both Rac1 and ubiquitylated-Rac1 bind to Tollip. xref These findings raise the interesting question of whether the ubiquitylation of Rac1 might modulate Tollip interactions."
sparser
"In line with this, it has been suggested that ubiquitylation might be involved in Rac1 dynamics in peripheral membrane ruffles and sorting of Rac1 in endocytic vesicles. xref , xref Further work will likely decipher the importance of Rac1 ubiquitylation not only as a restrictive regulation of its signaling, but also as a mean to modulate its interactions with effectors and with the membrane."
sparser
"Some studies have reported that the regulation of Rac1 drives diverse cellular processes during virus replication xref xref , and the ubiquitination and SUMOylation of Rac1 have been suggested to be involved in pseudopodial growth and the inhibition of virus replication xref xref ."
trips
"(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."
sparser
"Mechanistically, failure of lysosomal degradation of p62 and NBR1 leads to the phase separation of p62 and NBR1 accompanying the upregulation of p62 and NBR1 expressions and then promotes the formation of liquid droplets containing cIAP1, wherein cIAP1 promotes the Rac1 ubiquitination and degradation."
sparser
"The recent demonstration that group I PAK kinases repress the ubiquitination and degradation of Rac1 [59] suggests an even greater potential for this strategy, as PAK inhibition could lead to degradation of Rac1 and, consequentially, inhibition of signalling through multiple downstream effectors."
sparser
"RhoA is modified by ubiquitin ligase complexes directed by the E3 targeting proteins Smurf1 on K6 and K7, xref by FBXL19 on K135, xref and BACURD family proteins. xref Rac3 is ubiquitylated on K166 by the E3 protein FBXL19, xref while Rac1 is ubiquitylated by HACE on K147, xref XIAP and c-IAP1 on K147, xref and by FBXL19 on K166 dependent on S71 phosphorylation. xref Unlike the conservation of several tyrosine residues that undergo phosphorylation in multiple Rho GTPases, the positions of ubiquitylated lysines are not conserved ( xref ), and most identified ubiquitylation events occur in a “Ubiquitylation region” on the opposite side of the protein from the GTP-binding and switch regions ( xref )."
sparser
"Considering the E3 ligase catalytic activity of RNF19B, we speculated that RNF19B might be involved in DIRAS3-induced RAC1 degradation. xref A shows that the DIRAS3-induced upregulation of RAC1 ubiquitination was reversed after RNF19B knockdown by siRNA using co-immunoprecipitation assays in H1792 cells."
sparser
"Interestingly, co-immunoprecipitation analysis revealed that DIRAS3 promoted the interaction between RAC1 and RNF19B in 293FT cells compared with the interaction in control cells ( xref C), which might be the reason why DIRAS3 could induce ubiquitination and degradation of RAC1."
sparser
"RAC1 is the best known target of the HACE1 E3 ligase (Torrino et al , xref ; Mettouchi & Lemichez, xref ; Castillo‐Lluva et al , xref ; Daugaard et al , xref ; Goka & Lippman, xref ; Acosta et al , xref ), and HACE1 in part controls cell proliferation through direct ubiquitylation of RAC1, leading to its proteasomal degradation."
sparser
"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."
sparser
"A study revealed that MG53 exerts inhibitory effects on the malignant progression of hepatocellular carcinoma through its regulation of Ras-related C3 botulinum toxin substrate 1 (RAC1) ubiquitination and degradation while enhancing the chemosensitivity of hepatocellular carcinoma cells to sorafenib treatment by blocking the RAC1/mitogen-activated protein kinase signaling pathway ( xref )."
sparser
"MG53 regulates the ubiquitination and degradation of RAC1, a small GTPase with oncogenic function, this effect, in turn, inhibits the malignant progression of hepatocellular carcinoma and improves the resistance of hepatocellular carcinoma to sorafenib treatment by blocking the RAC1/MAPK signaling pathway ( xref )."
sparser
"Inhibition requires HACE1‐mediated ubiquitylation and degradation of the RAC1 (Ras‐related C3 botulinum toxin substrate 1) GTPase, previously identified as an E3 ligase substrate of HACE1 (Torrino et al , xref ; Mettouchi & Lemichez, xref ; Castillo‐Lluva et al , xref ; Daugaard et al , xref ; Goka & Lippman, xref ; Acosta et al , xref )."
sparser
"Altogether, these data identify critical amino-acids functional site in HACE1 ankyrin repeats 4 to 7 that control the interaction of HACE1 with Rac1, thereby establishing a correlation between the efficiency of interaction of Rac1 with HACE1 and the efficiency of ubiquitylation of Rac1 (R 2 = 0,87)."
sparser
"The data showed that MG53 could conjugate the poly-ubiquitination chain to RAC1 (Fig. xref ) and the endogenous ubiquitination assay showed that knockdown of MG53 could abrogate the ubiquitination modification of RAC1 in HCC cells (Fig. xref ), which indicated that MG53 could catalyze RAC1 ubiquitination modification in HCC cells."
sparser
"Although regulation of migration has been associated with Rac1 ubiquitination and subsequent proteasomal degradation in other cell models [ xref , xref , xref , xref ], we found that neither Rac1 levels were affected by KCTD5 depletion nor proteasome inhibition promoted Rac1 accumulation, independently of KCTD5 presence ( xref )."
sparser
"Conversely, CEP192 and γ‐tubulin enrichment weakens human embryonic kidney cells (HEK293T) motility. xref SCF mediates ubiquitination and degradation of Rac1, inhibiting tumor cell migration by suppressing lamellipodia formation. xref Fbxl19 down‐regulates Rac1, significantly reducing rat lung epithelial cells (MLE12) migration and migration front formation, while Mutants S71A‐Rac1 and K166R‐Rac1 resist degradation."