IndraLab

Statements

OTULIN is phosphorylated on Y56. 43 / 43
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"OTULIN Tyr-56 phosphorylation is counteracted by the activity of dual-specificity phosphatase 14 (DUSP14), which we identify as an OTULIN phosphatase that limits necroptosis."
31825842
sparser
"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
sparser
"These data suggest that c-Abl is activated in response to genotoxic treatment, which may be responsible for Tyr56 phosphorylation of OTULIN."
32770022
sparser
"Consistently, DNA-PKcs knockdown remarkably reduced OTULIN Tyr56 phosphorylation in cells treated with genotoxic drugs (Fig.  xref )."
32770022
sparser
"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 [59]."
33473179
sparser
"Consistently, ABL1 deletion in MDA-MB-231 cells suppressed OTULIN Tyr56 phosphorylation by Dox, CBP, and CPT-11 (Supplementary Fig.  xref )."
32770022
rlimsp
"The conserved Tyr56 of OTULIN makes critical contacts with the HOIP PUB domain, and its phosphorylation negatively regulates this interaction."
24726327
sparser
"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
sparser
"Such phosphorylation of OTULIN Tyr56 would regulate the general association of OTULIN with LUBAC before their recruitment to the TNFR complexes."
24726327
sparser
"In parallel, the decreased OTULIN association with HOIP correlated with increased OTULIN phosphorylation at Tyr56 upon genotoxic treatment (Supplementary Fig.  xref )."
32770022
sparser
"To further characterize the OTULIN phosphorylation upon genotoxic treatments, we developed an antibody specifically recognizing Tyr56 phosphorylation of OTULIN (4E−S4G)."
32770022
sparser
"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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"OTULIN phosphorylation at Tyr56 enhances its interaction with β-catenin while diminishing the OTULIN/LUBAC association."
32770022
sparser
"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
sparser
"The association with β-catenin is enhanced by OTULIN Tyr56 phosphorylation, which depends on genotoxic stress-activated ABL1/c-Abl."
32770022
sparser
"We found c-Abl is responsible for the Tyr56 phosphorylation of OTULIN upon DNA damage."
32770022
sparser
"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
sparser
"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
sparser
"Isothermal titration calorimetry (ITC) measurements demonstrated that phosphorylation of OTULIN on Tyr56 inhibits its interaction with the HOIP PUB domain."
24726327
rlimsp
"Consistent with the structure, phosphorylation of Tyr56 prevents interaction between OTULIN and HOIP 60, 71 (Fig. 2, bottom)."
26503766
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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
sparser
"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
sparser
"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
sparser
"DNA damage-induced c-Abl/ABL1 activation, which depends on DNA-PK, is required for Tyr56 phosphorylation of OTULIN."
32770022
sparser
"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
sparser
"It was previously reported that OTULIN Tyr56 is phosphorylated in cells ( Moritz et al., 2010 )."
24726327
sparser
"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
sparser
"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
sparser
"In addition, OTULIN becomes hyper-phosphorylated at Tyr56 upon induction of necroptosis, whereby it promotes necroptosis, supposedly by regulating RIPK1 Ub levels [ xref ]."
33288901
sparser
"We found knockdown of ABL1 significantly reduced OTULIN Tyr56 phosphorylation by Dox (Fig.  xref )."
32770022
sparser
"Our data suggest that DNA-PK/ABL1-mediated OTULIN Tyr56 phosphorylation is not required for Wnt3a-induced Wnt/β-catenin activation."
32770022
sparser
"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
sparser
"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
sparser
"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
sparser
"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
sparser
"OTULIN Tyr56 phosphorylation upon DNA damage promotes its association with β-catenin."
32770022
sparser
"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
sparser
"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
sparser
"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
sparser
"During necroptosis, OTULIN is hyper-phosphorylated at Tyr-56, which modulates RIPK1 ubiquitin dynamics and promotes cell death."
31825842
sparser
"Inhibiting c-Abl with imatinib also abrogated OTULIN Tyr56 phosphorylation in multiple TNBC cell lines and HBrt1071 PDX cells (Supplementary Fig.  xref )."
32770022
sparser
"Dox treatment induced a time-dependent OTULIN Tyr56 phosphorylation in MDA-MB 231 cells (Fig.  xref )."
32770022
sparser
"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