I{kappa}B kinase{beta} (IKBKB) Mutations in Lymphomas that constitutively activate Canonical nuclear factor {kappa}B (NF{kappa}B) signaling [Signal Transduction]

August 8th, 2014 by Kai, X., Chellappa, V., Donado, C., Reyon, D., Sekigami, Y., Ataca, D., Louissaint, A., Mattoo, H., Joung, J. K., Pillai, S.

Somatic mutations altering lysine 171 of the IKBKB gene that encodes IKKβ, the critical activating kinase in canonical NFκB signaling, have been described in splenic marginal zone lymphomas and multiple myeloma. Lysine 171 forms part of a cationic pocket that interacts with the activation loop phosphate in the activated wild type kinase. We show here that K171E IKKβ and K171T IKKβ represent kinases that are constitutively active even in the absence of activation loop phosphorylation. Predictive modeling and biochemical studies establish why mutations in a positively charged residue in the cationic pocket of an activation- loop phosphorylation dependent kinase result in constitutive activation. TALEN based knock-in mutagenesis provides evidence from a B lymphoid context that K171E IKKβ contributes to lymphomagenesis.
  • Posted in Journal of Biological Chemistry, Publications
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