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Related Experiment Videos

TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains.

Atsuhiro Kanayama1, Rashu B Seth, Lijun Sun

  • 1Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.

Molecular Cell
|August 26, 2004
PubMed
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TAB2 and TAB3 adaptor proteins bind to polyubiquitin chains via a zinc finger domain, activating TAK1 and IKK kinases. This reveals a new signaling mechanism for kinase regulation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Ubiquitination

Background:

  • NF-kappaB and IKK activation depend on TAK1 kinase complexed with TAB proteins.
  • TAK1 is activated by TRAF6, a ubiquitin ligase producing K63-linked polyubiquitin chains.

Purpose of the Study:

  • To investigate the role of TAB2 and TAB3 in TAK1/IKK activation.
  • To identify the mechanism by which TAB proteins bind polyubiquitin chains.

Main Methods:

  • Site-directed mutagenesis of the zinc finger (ZnF) domain in TAB2 and TAB3.
  • Assays to measure polyubiquitin binding and kinase activation (TAK1, IKK).
  • Functional analysis of domain-swapped TAB proteins and interaction with RIP.

Main Results:

Related Experiment Videos

  • TAB2 and TAB3 specifically bind lysine 63-linked polyubiquitin chains via their ZnF domain.
  • ZnF domain mutations abolish polyubiquitin binding and kinase activation.
  • Replacing the ZnF domain with other ubiquitin-binding domains restores function.
  • TAB2 interacts with polyubiquitinated RIP after TNFalpha stimulation.

Conclusions:

  • The ZnF domain of TAB2 and TAB3 acts as a polyubiquitin receptor.
  • Polyubiquitin binding domains represent a novel class of signaling modules.
  • This mechanism regulates protein kinase activity non-proteolytically.