The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation

Research output: Contribution to journalJournal articleResearchpeer-review

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The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation. / Paul, Indranil; Batth, Tanveer S; Iglesias-Gato, Diego; Al-Araimi, Amna; Al-Haddabi, Ibrahim; Alkharusi, Amira; Norstedt, Gunnar; Olsen, Jesper V; Zadjali, Fahad; Flores-Morales, Amilcar.

In: Scientific Reports, Vol. 7, 42800, 2017.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Paul, I, Batth, TS, Iglesias-Gato, D, Al-Araimi, A, Al-Haddabi, I, Alkharusi, A, Norstedt, G, Olsen, JV, Zadjali, F & Flores-Morales, A 2017, 'The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation', Scientific Reports, vol. 7, 42800. https://doi.org/10.1038/srep42800

APA

Paul, I., Batth, T. S., Iglesias-Gato, D., Al-Araimi, A., Al-Haddabi, I., Alkharusi, A., ... Flores-Morales, A. (2017). The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation. Scientific Reports, 7, [42800]. https://doi.org/10.1038/srep42800

Vancouver

Paul I, Batth TS, Iglesias-Gato D, Al-Araimi A, Al-Haddabi I, Alkharusi A et al. The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation. Scientific Reports. 2017;7. 42800. https://doi.org/10.1038/srep42800

Author

Paul, Indranil ; Batth, Tanveer S ; Iglesias-Gato, Diego ; Al-Araimi, Amna ; Al-Haddabi, Ibrahim ; Alkharusi, Amira ; Norstedt, Gunnar ; Olsen, Jesper V ; Zadjali, Fahad ; Flores-Morales, Amilcar. / The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation. In: Scientific Reports. 2017 ; Vol. 7.

Bibtex

@article{d85d7bd8a3fc4eac9928e3a7117a040b,
title = "The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation",
abstract = "SOCS2 is a pleiotropic E3 ligase. Its deficiency is associated with gigantism and organismal lethality upon inflammatory challenge. However, mechanistic understanding of SOCS2 function is dismal due to our unawareness of its protein substrates. We performed a mass spectrometry based proteomic profiling upon SOCS2 depletion and yield quantitative data for ~4200 proteins. Through this screen we identify a novel target of SOCS2, the serine-threonine kinase NDR1. Over-expression of SOCS2 accelerates turnover, while its knockdown stabilizes, endogenous NDR1 protein. SOCS2 interacts with NDR1 and promotes its degradation through K48-linked ubiquitination. Functionally, over-expression of SOCS2 antagonizes NDR1-induced TNFα-stimulated NF-κB activity. Conversely, depletion of NDR1 rescues the effect of SOCS2-deficiency on TNFα-induced NF-κB transactivation. Using a SOCS2(-/-) mice model of colitis we show that SOCS2-deficiency is pro-inflammatory and negatively correlates with NDR1 and nuclear p65 levels. Lastly, we provide evidence to suggest that NDR1 acts as an oncogene in prostate cancer. To the best of our knowledge, this is the first report of an identified E3 ligase for NDR1. These results might explain how SOCS2-deficiency leads to hyper-activation of NF-κB and downstream pathological implications and posits that SOCS2 induced degradation of NDR1 may act as a switch in restricting TNFα-NF-κB pathway.",
author = "Indranil Paul and Batth, {Tanveer S} and Diego Iglesias-Gato and Amna Al-Araimi and Ibrahim Al-Haddabi and Amira Alkharusi and Gunnar Norstedt and Olsen, {Jesper V} and Fahad Zadjali and Amilcar Flores-Morales",
year = "2017",
doi = "10.1038/srep42800",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - The ubiquitin ligase Cullin5SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation

AU - Paul, Indranil

AU - Batth, Tanveer S

AU - Iglesias-Gato, Diego

AU - Al-Araimi, Amna

AU - Al-Haddabi, Ibrahim

AU - Alkharusi, Amira

AU - Norstedt, Gunnar

AU - Olsen, Jesper V

AU - Zadjali, Fahad

AU - Flores-Morales, Amilcar

PY - 2017

Y1 - 2017

N2 - SOCS2 is a pleiotropic E3 ligase. Its deficiency is associated with gigantism and organismal lethality upon inflammatory challenge. However, mechanistic understanding of SOCS2 function is dismal due to our unawareness of its protein substrates. We performed a mass spectrometry based proteomic profiling upon SOCS2 depletion and yield quantitative data for ~4200 proteins. Through this screen we identify a novel target of SOCS2, the serine-threonine kinase NDR1. Over-expression of SOCS2 accelerates turnover, while its knockdown stabilizes, endogenous NDR1 protein. SOCS2 interacts with NDR1 and promotes its degradation through K48-linked ubiquitination. Functionally, over-expression of SOCS2 antagonizes NDR1-induced TNFα-stimulated NF-κB activity. Conversely, depletion of NDR1 rescues the effect of SOCS2-deficiency on TNFα-induced NF-κB transactivation. Using a SOCS2(-/-) mice model of colitis we show that SOCS2-deficiency is pro-inflammatory and negatively correlates with NDR1 and nuclear p65 levels. Lastly, we provide evidence to suggest that NDR1 acts as an oncogene in prostate cancer. To the best of our knowledge, this is the first report of an identified E3 ligase for NDR1. These results might explain how SOCS2-deficiency leads to hyper-activation of NF-κB and downstream pathological implications and posits that SOCS2 induced degradation of NDR1 may act as a switch in restricting TNFα-NF-κB pathway.

AB - SOCS2 is a pleiotropic E3 ligase. Its deficiency is associated with gigantism and organismal lethality upon inflammatory challenge. However, mechanistic understanding of SOCS2 function is dismal due to our unawareness of its protein substrates. We performed a mass spectrometry based proteomic profiling upon SOCS2 depletion and yield quantitative data for ~4200 proteins. Through this screen we identify a novel target of SOCS2, the serine-threonine kinase NDR1. Over-expression of SOCS2 accelerates turnover, while its knockdown stabilizes, endogenous NDR1 protein. SOCS2 interacts with NDR1 and promotes its degradation through K48-linked ubiquitination. Functionally, over-expression of SOCS2 antagonizes NDR1-induced TNFα-stimulated NF-κB activity. Conversely, depletion of NDR1 rescues the effect of SOCS2-deficiency on TNFα-induced NF-κB transactivation. Using a SOCS2(-/-) mice model of colitis we show that SOCS2-deficiency is pro-inflammatory and negatively correlates with NDR1 and nuclear p65 levels. Lastly, we provide evidence to suggest that NDR1 acts as an oncogene in prostate cancer. To the best of our knowledge, this is the first report of an identified E3 ligase for NDR1. These results might explain how SOCS2-deficiency leads to hyper-activation of NF-κB and downstream pathological implications and posits that SOCS2 induced degradation of NDR1 may act as a switch in restricting TNFα-NF-κB pathway.

U2 - 10.1038/srep42800

DO - 10.1038/srep42800

M3 - Journal article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 42800

ER -

ID: 174800655