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Statements

OTULIN is phosphorylated on Y56. 51 / 52
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"Interestingly, during necroptosis, OTULIN undergoes hyper-phosphorylation at Tyr-56, which affects RIPK1 ubiquitin dynamics and promotes cell death."
38199165
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"These data suggest that c-Abl is activated in response to genotoxic treatment, which may be responsible for Tyr56 phosphorylation of OTULIN."
32770022
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"Along with the increased OTULIN Tyr56 phosphorylation, β-catenin was also increased in cells treated with Dox, which was suppressed by c-Abl inhibitors or genetic deletion of ABL1 (Fig.  xref )."
32770022
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"In contrast, inhibiting c-Abl did not affect Wnt3a-induced β-catenin stabilization (Supplementary Fig.  xref , bottom panel), suggesting that c-Abl is specifically required for DNA damage-induced Wnt/β-catenin activation through mediating OTULIN Tyr56 phosphorylation."
32770022
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"Blocking OTULIN Tyr-56 phosphorylation did not affect the assembly of the necrosome ( Figure 5 D), which is consistent with previous reports demonstrating that LUBAC deficiency affected RIPK1 ubiquiti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
31825842
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"We found OTULIN Tyr56 phosphorylation in HEK293T cells and MDA-MB-231 cells, treated with Etop or Dox respectively, was abolished by DNA-PK inhibitor Nu7441, but not inhibitors of ATM (Ku55933), ATR (VE-821) or IKK (TPCA) (Supplementary Fig.  xref )."
32770022
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"Consistently, DNA-PKcs knockdown remarkably reduced OTULIN Tyr56 phosphorylation in cells treated with genotoxic drugs (Fig.  xref )."
32770022
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"Another consequence of the DNAPKsome-mediated cytoplasmic accumulation of c-Abl as a result of genotoxic stress is OTULIN phosphorylation at Tyr56, which may have critical outcomes xref ( xref )."
35958947
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"Our data suggest that DNA-PK/ABL1-mediated OTULIN Tyr56 phosphorylation is not required for Wnt3a-induced Wnt/β-catenin activation."
32770022
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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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"It was previously reported that OTULIN Tyr56 is phosphorylated in cells ( Moritz et al., 2010 )."
24726327
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"The association with β-catenin is enhanced by OTULIN Tyr56 phosphorylation, which depends on genotoxic stress-activated ABL1/c-Abl."
32770022
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"Although ATM is required for DNA-PK-mediated c-Abl phosphorylation and activation by IR xref , inhibiting DNA-PK, but not ATM, abolished OTULIN Tyr56 phosphorylation in response to genotoxic drug treatment."
32770022
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"Thus, DNA-PK-dependent c-Abl phosphorylation is essential for its activation and OTULIN phosphorylation at Tyr56 in response to genotoxic drugs, which plays a critical role in promoting Wnt/β-catenin activation and development of drug resistance in TNBC upon chemotherapy."
32770022
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"DNA damage-induced c-Abl/ABL1 activation, which depends on DNA-PK, is required for Tyr56 phosphorylation of OTULIN."
32770022
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"OTULIN phosphorylation at Tyr56 enhances its interaction with β-catenin while diminishing the OTULIN/LUBAC association."
32770022
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"TNF induces the phosphorylation of OTULIN on Y56 by an unknown kinase, inhibiting the interaction between OTULIN and HOIP to stabilize the linear ubiquitination complex [172,173] ."
30452908
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"Interestingly, OTULIN is hyper-phosphorylated at Tyr56 during necroptosis, pointing towards a role of OTULIN Tyr56 phosphorylation in the regulation of necroptotic cell death [ xref ] (see below)."
33288901
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"Using cell-free assays, two groups have proposed that OTULIN could be phosphorylated on Tyr-56 ( Schaeffer et al., 2014; Elliott et al., 2014 )."
31825842
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"This is also the case when OTULIN is phosphorylated at Tyr56 and in cells expressing the binding mutant OTULIN Y56F, both of which disrupt the OTULIN–HOIP interaction [ xref , xref ]."
33288901
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"In addition, OTULIN becomes hyper-phosphorylated at Tyr56 upon induction of necroptosis, whereby it promotes necroptosis, supposedly by regulating RIPK1 Ub levels [ xref ]."
33288901
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"This interaction is negatively regulated by phosphorylation of OTULIN on Y56, thereby disrupting binding to HOIP and abrogating OTULIN-dependent suppression of LUBAC [ 29 , 30 ]."
34074601
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"Evidence for the phosphorylation of OTULIN Tyr56 in vivo has been reported ( Moritz et al., 2010 ), but it is still unclear which enzymes are responsible for placing and removing this phosphorylation."
24726327
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"OTULIN Tyr56 phosphorylation upon DNA damage promotes its association with β-catenin."
32770022
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"Such phosphorylation of OTULIN Tyr56 would regulate the general association of OTULIN with LUBAC before their recruitment to the TNFR complexes."
24726327
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"This approach revealed that OTULIN was phosphorylated on Tyr-56, among other sites, upon necroptotic stimulation ( Figure 4 C)."
31825842
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"Moreover, a phospho-mimetic mutation on Tyr56 (Y56D) also abolished the association between OTULIN and HOIP, suggesting that genotoxic treatment may induce OTULIN phosphorylation at Tyr56, which disrupts the OTULIN-HOIP association."
32770022
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"OTULIN is phosphorylated at tyrosine 56 (Y56) located in the PUB domain-interacting motif (PIM)."
38017534
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"However, while the Y56D mutation decreased OTULIN interaction with HOIP, it enhanced OTULIN association with β-catenin (Fig.  xref and Supplementary Fig.  xref ), suggesting that OTULIN Tyr56 phosphorylation may promote OTULIN interaction with β-catenin."
32770022
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"Consistently, we found OTULIN Tyrosine phosphorylation at Y56 was induced upon genotoxic treatments (Supplementary Fig.  xref ), which was correlated with the increased association between OTULIN and β-catenin (Fig.  xref )."
32770022
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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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"Similarly, DNA damage-induced ABL1/c-Abl (ABL proto-oncogene 1) activation can promote the phosphorylation of OTULIN at Tyr56, which enhances its interaction with β-catenin and blocks its binding to LUBAC ( xref ; xref ; xref )."
34177595
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"Interestingly, OTULIN is hyper-phosphorylated at Y56 during necroptosis and counteracted by the dual specificity protein phosphatase 14 (DUSP14) [ xref ]."
38017534
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"Dox treatment induced a time-dependent OTULIN Tyr56 phosphorylation in MDA-MB 231 cells (Fig.  xref )."
32770022
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"Moreover, OTULIN phosphorylation at Tyr56 by the tyrosine protein kinase ABL1 enhances its interaction with β-catenin while diminishing its association with HOIP, which inhibits β-catenin Met1-Ub and its degradation to promote Wnt/β-Catenin activation (Wang et al. xref )."
39281196
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"Phosphorylation of OTULIN on Tyr56 by the kinase Abl-1 disrupts the interaction of OTULIN with LUBAC, enabling OTULIN binding to β-catenin in MDA-MB-231 cells [ 31 ]."
34074601
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"Moreover, the phosphorylation of Tyr56 in OTULIN is increased, and this is counteracted by the dual-specificity phosphatase 14 (DUSP14) during necroptosis [ xref ]."
32403254
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"To identify the kinase that is responsible for the OTULIN Tyr56 phosphorylation in response to DNA damage, we performed a siRNA screen with a tyrosine kinase sub-library, which consists of 88 tyrosine kinases."
32770022
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"We found knockdown of ABL1 significantly reduced OTULIN Tyr56 phosphorylation by Dox (Fig.  xref )."
32770022
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"Importantly, depleting ABL1 in MDA-MB-231 cells abolished Dox-induced OTULIN Tyr56 phosphorylation, which was rescued by ABL1-WT but not kinase-dead K290R mutant (Fig.  xref )."
32770022
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"With a complimentary screen with a variety of tyrosine kinase inhibitors, we confirmed that inhibiting ABL1/c-Abl with dasatinib abrogated OTULIN Tyr56 phosphorylation in response to Dox (Supplementary Fig.  xref )."
32770022
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"Inhibiting c-Abl with imatinib also abrogated OTULIN Tyr56 phosphorylation in multiple TNBC cell lines and HBrt1071 PDX cells (Supplementary Fig.  xref )."
32770022
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"Consistently, ABL1 deletion in MDA-MB-231 cells suppressed OTULIN Tyr56 phosphorylation by Dox, CBP, and CPT-11 (Supplementary Fig.  xref )."
32770022
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"Supporting this notion, the phosphorylation of Y56 in OTULIN is reported to increase after cells were induced to undergo necroptosis (by treatment with TNF  +  cycloheximide+ the pan-caspase inhibitor zVAD-fmk), and, the phosphatase DUSP14 was found to counteract the phosphorylation [ xref ]."
33473179
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"Isothermal titration calorimetry (ITC) measurements demonstrated that phosphorylation of OTULIN on Tyr56 inhibits its interaction with the HOIP PUB domain."
24726327
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"Conversely, during necroptosis, OTULIN undergoes hyperphosphorylation at the Tyr56 site, augmenting RIPK1 ubiquitination and promoting cell death."
40007541
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"In parallel, the decreased OTULIN association with HOIP correlated with increased OTULIN phosphorylation at Tyr56 upon genotoxic treatment (Supplementary Fig.  xref )."
32770022
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"Additionally, a study also reported that OTULIN is hyper-phosphorylated at Tyr56 residues during necroptosis, which can modulate ubiquitination of the receptor interacting protein kinase (RIPK1) and promote cell death ( xref )."
34177595
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"Taken together, these data support that OTULIN phosphorylation at Tyr56 upon DNA damage enhances its interaction with β-catenin while disrupting OTULIN/HOIP association, resulting in increased β-catenin stability and Wnt/β-catenin-dependent transcriptional upregulation."
32770022
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"This phosphorylation of OTULIN’s Tyr56 can be counteracted by DUSP14 ( xref )."
40007541
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"We found c-Abl is responsible for the Tyr56 phosphorylation of OTULIN upon DNA damage."
32770022