IndraLab

Statements

OTUB2 is sumoylated. 44 / 44
| 1 43
sparser
"Targeting OTUB2 sumoylation could reduce its ability to interact with YAP/TAZ, resulting in YAP/TAZ degradation."
31832513
sparser
"A yet-unknown SUMO-interacting motif (SIM) in YAP and TAZ was required for the association of YAP/TAZ with SUMOylated OTUB2."
36264492
sparser
"Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activate YAP/TAZ."
36264492
sparser
"Accordingly, we found the EGF stimulation, but not the treatment of other cytokines, specifically induced OTUB2 SUMOylation ( Figure 7 B); this was confirmed in PLA analysis ( Figure S7 A)."
30472188
sparser
"In addition, sumoylation of OTUB2, a deubiquitinase participating in the maintenance of several CSCs, enables its interaction with transcriptional regulators YAP/TAZ to activate YAP/TAZ signaling and promote cancer cell stemness ( xref )."
36601585
sparser
"Poly-SUMOylated OTUB2, which was induced by Epidermal growth factor (EGF) and oncogenic KRAS, was shown to bind and activate YAP/TAZ promoting tumor metastasis [ xref ]."
31619007
sparser
"KRAS has been shown to indirectly activate Yes-associated protein (YAP), the downstream effector of the Hippo pathway, by inducing OTUB2 poly-SUMOylation, which can regulate gene expression and cellular proliferation xref ."
38481800
sparser
"The levels of SUMOylated OTUB2 were significantly higher in KRAS-high and KRAS-mutated samples, and they were positively correlated with the levels of YAP and TAZ ( Figures 7 I, 7J, and S7 E)."
30472188
sparser
"Thus, these clinical data support our model that EGF signaling or RAS activation stimulates OTUB2 SUMOylation and thereby stabilizes YAP/TAZ, which enhances cancer stemness and metastasis ( Figure 7 K[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30472188
sparser
"The OTUB2 SUMOylation site is located in the last five amino acid residues, which have been reported to cause OTUB2 self-inhibition ( Balakirev et al., 2003 )."
30472188
sparser
"We show that C-terminal SUMO conjugation resulting in the artificial OTUB2 C-terminal SUMOylation seems to create a binding bridge for YAP/TAZ, but does not directly stimulates OTUB2 DUB activity."
30472188
sparser
"Importantly, the SUMOylation-deficient OTUB2 K233R cannot promote tumor metastasis as circulating tumor cells are reduced in mice, indicating that OTUB2 SUMOylation is a key mechanism for regulation b[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30472188
sparser
"In this study we discovered that OTUB2 SUMOylation is promoted by KRAS mutation."
30472188
sparser
"Sumoylated OTUB2 interacts specifically with yet-unidentified sumo interaction motifs (SIMs) in WW domain-containing transcription factor (TAZ) and Yes-associated protein (YAP) to regulate protein activity and TAZ/YAP polyubiquitination in a Hippo-independent manner."
35110531
sparser
"In breast cancer patients, there is a good correlation between the levels of KRAS and the levels of OTUB2 sumoylation as wells as the levels of Yap/Taz protein expression ( xref )."
33869224
sparser
"Hence, OTUB2 sumoylation represents a novel mechanism that links the oncogenic EGFR-RAS pathway to Yap/Taz activation and a potential therapeutic target for cancer treatment."
33869224
sparser
"Combined with our previous observations, these results suggest that OTUB2 SUMOylation is critical for its observed pro-oncogenic activity."
30472188
sparser
"Additionally, EGF therapy or KRAS mutation stabilizes YAP/TAZ expression and OTUB2 sumoylation [ xref ]."
35110531
sparser
"Our observations reveal a potential mechanism of YAP/TAZ activation by oncogenic KRAS, as OTUB2 SUMOylation should stabilize YAP/TAZ by promoting their interaction with and deubiquitination by the SUM[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30472188
sparser
"Moreover, we found that EGF, which can activate RAS, also promotes OTUB2 SUMOylation."
30472188
sparser
"We posit that oncogenic signals generated from activated RAS or EGFR may in part be mediated by YAP/TAZ activation via OTUB2 SUMOylation."
30472188
sparser
"Additionally, Josephin domain-containing protein 2 (JOSD2) and poly-SUMOylated OTU deubiquitinase ubiquitin aldehyde binding 2 (OTUB2) deubiquitinate and stabilize YAP/TAZ [ xref , xref ]."
37743467
sparser
"We have also identified an as yet unknown SIM domain in YAP/TAZ that mediates the specific binding between YAP/TAZ and SUMOylated OTUB2 and thereby controls YAP/TAZ poly-ubiquitination and protein act[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30472188
sparser
"This occurs through the binding of SUMOylated OTUB2 to YAP through its SUMO-interacting motif."
38136274
sparser
"Together, these results suggest that SUMOylation of OTUB2 is both necessary and sufficient for its ability to bind to YAP/TAZ."
30472188
sparser
"OTUB2 is polysumoylated at position lysine 233, and there may be a SUMO, or small ubiquitin-related modifier, interacting motif (SIM) in YAP1/TAZ, which may play an important role in its interaction combining this domain with sumoylated OTUB2."
35850645
sparser
"Recently, OTUB2 has been shown to bind directly to and activate YAP/TAZ. xref For this interaction to occur, OTUB2 must be sumoylated."
31832513
sparser
"In breast cancer cells, endogenous OTUB2 was also found to be poly-SUMOylated ( Figure 4 D)."
30472188
sparser
"Moreover, substitution of the putative SUMOylation site Lys233 by an arginine (OTUB2-K233R) completely blocked the SUMOylation of OTUB2 ( Figure 4 E)."
30472188
sparser
"PLA staining was performed to determine the levels of OTUB2 SUMOylation, and the IHC staining to determine the protein levels of YAP and TAZ."
30472188
sparser
"To determine the subcellular location of SUMOylated OTUB2, we performed proximity ligation assay (PLA), which enables detection of protein modification in situ with high specificity and sensitivity ( [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30472188
sparser
"Homozygosity for this K233R mutation was confirmed by Sanger sequencing, and immunoblot analysis confirmed the absence of OTUB2 SUMOylation in the K233R KI cells ( Figure S5 K)."
30472188
sparser
"We next examined whether the YAP/TAZ SIM is needed for binding to SUMOylated OTUB2."
30472188
sparser
"We propose that the YAP/TAZ SIM is critical for YAP/TAZ function due to its interaction with SUMOylated OTUB2 for YAP/TAZ stabilization."
30472188
sparser
"Moreover, expression of OTUB2-WT or OTUB2-SUMO3 could not increase mammosphere numbers in cells expressing YAP/TAZ-SIM3A ( Figures S6 F and S6G), indicating that the SIM of YAP/TAZ is required to func[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30472188
sparser
"The sumoylation of OTUB2 allows it to interact with the sumoylation interaction motif found in YAP/TAZ."
31832513
sparser
"We then examined roles of the two major EGF-dependent molecular pathways, PI3K-AKT and RAS-RAF in OTUB2 SUMOylation."
30472188
reach
"Indeed, co-expression of Flag-OTUB2 and Myc-SUMO3 resulted in OTUB2 poly-SUMoylation, which could be strongly enhanced by co-expression of PIAS3 ( Figure 4 B) and decreased by SENP1 ( Figure 4 C)."
30472188
sparser
"Strikingly, active KRAS-G12V, but not the PI3K-AKT or the constitutively active Myr-AKT, strongly potentiated OTUB2 SUMOylation in HEK293T and HeLa cells ( Figures 7 C and 7D; data not shown)."
30472188
sparser
"Therefore, our observations suggest that EGF and RAS activation might be able to regulate YAP/TAZ through SUMOylating OTUB2."
30472188
sparser
"To examine whether OTUB2 SUMOylation is needed for EGF-stimulated metastasis, we in vitro pretreated parental 4T1 cells and SUMOylation-deficient OTUB2 K233R KI cells with EGF before injecting them in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30472188
sparser
"Indeed, co-expression of Flag-OTUB2 and Myc-SUMO3 resulted in OTUB2 poly-SUMoylation, which could be strongly enhanced by co-expression of PIAS3 ( Figure 4 B) and decreased by SENP1 ( Figure 4 C)."
30472188
sparser
"These results further implicate SUMOylated OTUB2 in EGF-stimulated metastasis."
30472188
sparser
"Moreover, Myc-SUMO3 transfection resulted in OTUB2 poly-SUMOylation, which was significantly decreased by the SUMO-specific protease SENP1 ( xref B)."
39776804