title: IκB kinase β (IKBKB) mutations in lymphomas that constitutively activate canonical nuclear factor κB (NFκB) signaling.
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.
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129.
authors.forename: Xin
authors.initials: X
authors.lastname: Kai
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129.
authors.forename: Vasant
authors.initials: V
authors.lastname: Chellappa
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129.
authors.forename: Carlos
authors.initials: C
authors.lastname: Donado
authors.affiliation: Molecular Pathology Unit, Massachusetts General Hospital, Boston, Massachusetts 02129, and.
authors.forename: Deepak
authors.initials: D
authors.lastname: Reyon
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129.
authors.forename: Yurie
authors.initials: Y
authors.lastname: Sekigami
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129.
authors.forename: Dalya
authors.initials: D
authors.lastname: Ataca
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Abner
authors.initials: A
authors.lastname: Louissaint
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mattoo
authors.affiliation: Molecular Pathology Unit, Massachusetts General Hospital, Boston, Massachusetts 02129, and; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Joung
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129,. Electronic address: pillai@helix.mgh.harvard.edu.
authors.forename: Shiv
authors.initials: S
authors.lastname: Pillai
mesh_terms: D019943:Amino Acid Substitution; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D051550:I-kappa B Kinase; C496560:IKBKB protein, human
keywords: I Kappa B Kinase Beta; Lymphoma; Molecular Modeling; Mutant; NF-kappa B (NF-κB); Protein Kinase; Serine/Threonine Protein Kinase; Signaling; Transcription Activator-like Effector Nuclease (TALEN)
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