The ubiquitin ligase Cullin5 SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation

Indranil Paul, Tanveer S. Batth, Diego Iglesias-Gato, Amna Al-Araimi, Ibrahim Al-Haddabi, Amira Alkharusi, Gunnar Norstedt, Jesper V. Olsen, Fahad Zadjali, Amilcar Flores-Morales

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number42800
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - Feb 20 2017

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Ligases
Ubiquitin
Transcriptional Activation
Ubiquitin-Protein Ligases
Gigantism
Proteins
Protein-Serine-Threonine Kinases
Ubiquitination
Colitis
Oncogenes
Proteomics
Mass Spectrometry
Prostatic Neoplasms

ASJC Scopus subject areas

  • General

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The ubiquitin ligase Cullin5 SOCS2 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, 20.02.2017.

Research output: Contribution to journalArticle

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 Cullin5 SOCS2 regulates NDR1/STK38 stability and NF-κB transactivation. In: Scientific Reports. 2017 ; Vol. 7.
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