Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-κB activation

Science. 2014 May 16;344(6185):760-4. doi: 10.1126/science.1250020.

Abstract

A switchlike response in nuclear factor-κB (NF-κB) activity implies the existence of a threshold in the NF-κB signaling module. We show that the CARD-containing MAGUK protein 1 (CARMA1, also called CARD11)-TAK1 (MAP3K7)-inhibitor of NF-κB (IκB) kinase-β (IKKβ) module is a switch mechanism for NF-κB activation in B cell receptor (BCR) signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKKβ to TAK1, generating a steep dose response to BCR stimulation. Mutation of the scaffolding protein CARMA1 at serine-578, an IKKβ target, abrogated not only late TAK1 activity, but also the switchlike activation of NF-κB in single cells, suggesting that phosphorylation of this residue accounts for the feedback.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / metabolism*
  • Cell Line
  • Chickens
  • Feedback, Physiological
  • Guanylate Cyclase / genetics
  • Guanylate Cyclase / metabolism*
  • I-kappa B Kinase / metabolism*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Mice, Knockout
  • Mutation
  • NF-kappa B / agonists*
  • Phosphorylation
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / metabolism*
  • Serine / genetics
  • Serine / metabolism
  • Signal Transduction

Substances

  • CARD Signaling Adaptor Proteins
  • NF-kappa B
  • Receptors, Antigen, B-Cell
  • Serine
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Guanylate Cyclase

Associated data

  • GEO/GSE41176