IκB Kinase β (IKBKB) Mutations in Lymphomas That Constitutively Activate Canonical Nuclear Factor κB (NFκB) Signaling
Year: 2014
Type: article
Abstract: 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. Transcription activator-like effector nuclease-based knock-in mutagenesis provides evidence from a B lymphoid context that K171E IKKβ contributes to lymphomagenesis.
Source: Journal of Biological Chemistry
Institutions: Harvard University, Massachusetts General Hospital
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G1347999300, G1907037579, Studies on Peripheral B Lymphocyte Development, Advancing stem cell technologies using engineered zinc finger proteins, G318341812, Molecular determinants of prognosis in limited-stage follicular lymphoma, Mutations in the SIAE Gene and Susceptibility to Autoimmune Diseases
OpenAlex ID: W2034085982