IndraLab
Statements
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"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
"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
"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
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"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
"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
"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."
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"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)."
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."
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"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 ."
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
"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."