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ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress

Zhao-Hui Wu1, Ee Tsin Wong, Yuling Shi

  • 1Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA. zwu6@uthsc.edu

Molecular Cell
|October 12, 2010
PubMed

Insights

Genotoxic stimuli activate NF-κB survival pathways via ATM and IKK. This study reveals ELKS ubiquitination as a key molecular link, assembling essential protein complexes for NF-κB activation.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • The transcription factor NF-κB regulates cancer cell survival following genotoxic stress.
  • This pathway involves ATM kinase and IκB kinase (IKK), but the molecular link is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism connecting ATM and IKK activation.
  • To identify key proteins and modifications involved in the NF-κB response to genotoxic stimuli.

Main Methods:

  • Investigated protein interactions and ubiquitination events in response to genotoxic stimuli.
  • Utilized genetic mutations and protein complex analysis to dissect the signaling pathway.

Main Results:

  • Demonstrated that ATM activates TAK1 kinase through a complex involving IKKγ/NEMO and ELKS.
  • Showed that K63-linked polyubiquitination of ELKS by XIAP and UBC13 is crucial for TAK1 association.
  • Identified that NEMO's ubiquitin-binding function is essential for ELKS interaction and subsequent IKK activation.

Conclusions:

  • ATM and NEMO-dependent ubiquitination of ELKS is critical for assembling the TAK1/TAB2/3 and NEMO/IKK complexes.
  • This ubiquitination-dependent complex assembly mediates IKK and NF-κB activation following genotoxic stress, clarifying a key survival pathway in cancer cells.

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