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Statements

OTULIN is phosphorylated. 55 / 57
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"The phosphorylation of ABL1-dependent OTULIN (OTU deubiquitinase with linear linkage specificity) induces β-catenin activation following damage to the DNA, promoting drug resistance in triple-negative breast cancer ( xref )."
35719027
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"Phosphorylation of OTULIN (OTU deubiquitinase with linear linkage specificity) upon DNA damage drives β-catenin activation, thus promoting drug resistance in TNBC [ xref ]."
37667382
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"This OTULIN phosphorylation promotes genotoxic Wnt/β-catenin activation and enhances drug resistance in breast cancers [ xref ]."
38017534
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"Notably, neither mutation of Tyr56 nor phosphorylation of OTULIN affects the catalytic activity of OTULIN in vitro [ xref , xref ], suggesting that Tyr56 phosphorylation mainly regulates the OTULIN–LUBAC interaction."
33288901
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"OTULIN is phosphorylated during necroptosis, which is inhibited by the phosphatase DUSP14 to suppress cell death [ xref ]."
33919439
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"However, the signals governing OTULIN phosphorylation and its role in OTULIN-mediated processes remain unknown."
31825842
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"Phosphorylated OTULIN displaces SPATA2-CYLD from HOIP, converging on the regulation of necroptotic RIPK1 activation and ubiquitination."
31825842
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"Third, we show that OTULIN phosphorylation is counteracted by the dual-specificity phosphatase DUSP14, which we identify as an OTULIN phosphatase that limits cell death."
31825842
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"Although the protein kinases and phosphatases responsible for the dynamics of OTULIN phosphorylation and LUBAC activation have not yet been identified, the DNA-damage activated kinase ABL1 was recentl[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34074601
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"To confirm that OTULIN was tyrosine phosphorylated in response to TCZ, we immunoprecipitated OTULIN under denaturing conditions and assessed its reactivity with an anti-phospho-tyrosine antibody."
31825842
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"We found that OTULIN was indeed hyper-phosphorylated in TCZ-treated cells ( Figure 4 B)."
31825842
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"Additionally, DNA damage-induced ABL1/c-Abl (ABL proto-oncogene 1) activation can promote the phosphorylation of OTULIN, which enhances its interaction with β-catenin and promotes the activation of Wnt/β-catenin signalling ( xref ) This mechanism plays a critical role in the triple-negative breast cancer (TNBC) progression, metastasis, and drug resistance to cancer treatments ( xref ; xref ; xref )."
34177595
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"Mutation of Tyr-56 to a non-phosphorylatable phenylalanine (Y56F) and stable re-expression in shOTULIN cells revealed that Tyr-56 mutation completely abrogated OTULIN phosphorylation during necroptosi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
31825842
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"For example, OTULIN might be specifically phosphorylated after the recruitment to the TNFR as part of an active exclusion mechanism."
24726327
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"While investigating OTULIN phosphorylation, we noticed that this modification was markedly influenced by cell density."
31825842
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"When cells were treated at 50%–60% confluence, OTULIN phosphorylation was enhanced following TCZ stimulation; conversely, no increase was observed when cells were fully confluent ( Figure S5 B)."
31825842
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"As such, sub-confluence was chosen as the more physiologically relevant condition for investigating the role of OTULIN phosphorylation in cell death."
31825842
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"To further characterize the OTULIN phosphorylation upon genotoxic treatments, we developed an antibody specifically recognizing Tyr56 phosphorylation of OTULIN (4E−S4G)."
32770022
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"This antibody detected OTULIN phosphorylation in cells exposed to genotoxic drugs, which was abrogated by phosphatase treatment or Tyr56 mutation."
32770022
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"We next examined whether and how OTULIN phosphorylation affected necroptosis."
31825842
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"Therefore, targeting OTULIN or OTULIN phosphorylation may serve as an effective strategy for the treatment of patients with TNBC ( xref ; xref )."
34177595
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"Accordingly, we observed a decrease in linear ubiquitination of β-catenin with comparable kinetics in cells treated with Dox, which correlated with the increase of OTULIN phosphorylation (Fig.  xref )."
32770022
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"Wnt3a treatment induced a decrease of β-catenin linear ubiquitination with much-delayed kinetics (Supplementary Fig.  xref ), which may be due to, at least in part, the lack of OTULIN phosphorylation."
32770022
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"OTULIN hyper-phosphorylation promotes necroptosis by locking ring finger protein 31 (RNF31, also known as HOIP) away from the cylindromatosis (CYLD) complex, resulting in altered receptor interacting serine/threonine kinase 1 (RIPK1) ubiquitination."
32944611
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"We observed that RIPK1 and MLKL phosphorylation were blunted in cells expressing Y56F OTULIN, particularly at later time points when we observed peak OTULIN phosphorylation ( Figure 5 A)."
31825842
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"LUBAC-OTULIN complex formation can depend on phosphorylation of the OTULIN PIM domain [ 29 , 30 ], and hyperphosphorylation of OTULIN can modulate RIPK1 ubiquitination, thereby promoting necroptotic c[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
34074601
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"While assembly of the necrosome was not affected by impaired OTULIN phosphorylation ( Figure 5 D), RIPK1 was less active in the necrosome of Y56F OTULIN cells ( Figure 5 D)."
31825842
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"However, the kinases and phosphatases responsible for regulating OTULIN phosphorylation remain unknown and should be identified."
34074601
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"How is phosphorylation of OTULIN regulated?"
34074601
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"To examine how OTULIN phosphorylation affected RIPK1 ubiquitin dynamics during necroptosis, we performed TUBE enrichment."
31825842
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"DNA damage-activated c-Abl is required for OTULIN phosphorylation."
32770022
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"ABL1-dependent OTULIN phosphorylation promotes genotoxic Wnt/beta-catenin activation to enhance drug resistance in breast cancers."
32770022
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"Further investigations are needed to elucidate in more detail the consequence of the OTULIN phosphorylation and how it is regulated."
33473179
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"To characterize whether OTULIN phosphorylation affected its intrinsic catalytic activity, we immunoprecipitated OTULIN from untreated (UT) or TCZ-treated cells and examined its activity in cleaving Me[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
31825842
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"OTULIN activity was equivalent in both conditions ( Figure S6 A), suggesting that OTULIN phosphorylation does not modulate its DUB activity per se."
31825842
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"These data suggest that phosphorylation of OTULIN regulates RIPK1 ubiquitin dynamics during necroptosis by modulating differential DUB interaction with LUBAC."
31825842
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"Phosphorylation of OTULIN likely involves dynamic action of kinases and phosphatases."
31825842
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"We observed OTULIN phosphorylation in the cytoplasm along with increased cytoplasmic c-Abl level at later time points after Dox treatment, suggesting that c-Abl may translocate into the cytoplasm after its nuclear activation upon genotoxic stress and promote OTULIN phosphorylation (Supplementary Fig.  xref and xref )."
32770022
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"Co-expression of DUSP14 abolished OTULIN phosphorylation in HEK239T cells ( Figure 6 B), which was reversed when using the C111S DUSP14 catalytically inactive mutant or when cells were treated with th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
31825842
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"DUSP inhibition alone was sufficient to promote OTULIN phosphorylation in HaCaT cells ( Figure 6 D, lane 3), which was not further enhanced upon TCZ stimulation ( Figure 6 D, lane 4)."
31825842
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"This is concordant with our observation that disruption of OTULIN phosphorylation did not affect RIPK1 Ser-166 phosphorylation at early time points ( Figure 5 A)."
31825842
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"Phosphorylation of OTULIN promotes genotoxicity-induced Wnt/β-catenin activation, which plays a critical role in cancer progression, metastasis, and drug resistance xref ."
39333335
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"This observation was further confirmed by our in vitro c-Abl kinase assay showing that Dox-induced OTULIN phosphorylation was suppressed by inhibiting DNA-PK, which was comparable to that in cells treated with imatinib (Supplementary Fig.  xref )."
32770022
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"In relation to ubiquitination, Wang et al . demonstrated that a genotoxic effect from chemotherapy could inhibit the phosphorylation of c-Abl2 and OTULIN (OTU Deubiquitinase with Linear Linkage Specificity) to encourage linear ubiquitination of β-catenin regardless of the FZD/LRP heterodimeric receptors and Wnt ligands in breast cancer. xref Phosphorylated OTULIN is known to be bound to the ubiquitin ligase complex, LUBAC (Linear ubiquitin chain assembly complex: SHARPIN, HOIL-IL, and HOIP), which hinders the ubiquitination of β-catenin to stabilize the Wnt/β-catenin signaling pathway to promote tumorigenesis. xref In our study, we proved that both gemcitabine and niclosamide enhance the activated levels of β-catenin destruction complex and ubiquitin to induce anti-tumorigenesis."
37917550
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"Therefore, we propose that the phosphorylation of OTULIN commits the cell to necroptosis once RIPK1 has been activated."
31825842
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"Therefore, it would be intriguing to explore whether both niclosamide – gemcitabine and inhibition of OTULIN phosphorylation could synergistically strengthen the level of β-catenin ubiquitination with the induced genotoxic stress from niclosamide – gemcitabine."
37917550
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"Inhibition of DUSP activity promoted OTULIN phosphorylation, which was not furthered with TCZ, suggesting that inactivation of DUSP14 during cell death may be a primary mechanism through which OTULIN [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
31825842
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"OTULIN deficiency leads to excessive linear ubiquitination on proteasome subunits, which disrupts proteasome assembly and function. xref Therefore, Ty56 phosphorylation of OTULIN may increase its DUB activity on the proteasome, potentiating the ubiquitin-proteasome system (UPS) activity that may have profound effects on oncogenesis. xref "
35958947
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"Phosphorylation of OTULIN regulates RIPK1 ubiquitination and promotes necroptosis ( xref )."
34797715
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"Phosphorylation of OTULIN tyrosine 56 (Y56P) in the PIM domain prevents its binding with HOIP-LUBAC, therefore impairing OTULIN-mediated LUBAC regulation ( xref )."
35764170
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"Furthermore, while OTULIN and the HOIP PUB domain form a gel filtration‐stable complex in vitro , the majority of OTULIN in cell lysates does not coelute with LUBAC indicating that OTULIN may be phosphorylated in cells, and dephosphorylation of OTULIN in cell extracts led to coelution of OTULIN with LUBAC xref ."
26503766
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"However, a physiological relevance of phosphorylation has not been shown so far nor has a kinase capable of phosphorylating OTULIN been identified."
28446710
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"We speculate that the genotoxic stress-induced OTULIN phosphorylation at Tyr56 may not only increase the interaction between OTULIN and β-catenin but also enhance the LUBAC autoubiquitination and self-inhibition through dissociation from HOIP xref , which render OTULIN highly efficient in promoting β-catenin deubiquitination and stabilization upon DNA damage."
32770022
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"Consistently, phosphorylation of the equivalent residue in OTULIN abolishes the interaction with HOIP [ xref ]."
27913667
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"Thus, stimulation-associated tyrosine phosphorylation of OTULIN, including at Tyr56, cannot be responsible for OTULIN’s absence from SCs."
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