Bruton's tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement

J Exp Med. 2000 May 15;191(10):1745-54. doi: 10.1084/jem.191.10.1745.

Abstract

Mutations in the gene encoding Bruton's tyrosine kinase (btk) cause the B cell deficiency diseases X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. In vivo and in vitro studies indicate that the BTK protein is essential for B cell survival, cell cycle progression, and proliferation in response to B cell antigen receptor (BCR) stimulation. BCR stimulation leads to the activation of transcription factor nuclear factor (NF)-kappaB, which in turn regulates genes controlling B cell growth. We now demonstrate that a null mutation in btk known to cause the xid phenotype prevents BCR-induced activation of NF-kappaB. This defect can be rescued by reconstitution with wild-type BTK. This mutation also interferes with BCR-directed activation of IkappaB kinase (IKK), which normally targets the NF-kappaB inhibitor IkappaBalpha for degradation. Taken together, these findings indicate that BTK couples IKK and NF-kappaB to the BCR. Interference with this coupling mechanism may contribute to the B cell deficiencies observed in XLA and xid.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Agammaglobulinemia / genetics
  • Agammaglobulinemia / immunology
  • Agammaglobulinemia / metabolism
  • Animals
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism*
  • Base Sequence
  • Cell Line
  • Chickens
  • DNA Primers / genetics
  • Enzyme Activation
  • Humans
  • I-kappa B Kinase
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology
  • Immunologic Deficiency Syndromes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / deficiency
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction

Substances

  • DNA Primers
  • NF-kappa B
  • Receptors, Antigen, B-Cell
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Btk protein, mouse
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • Chuk protein, mouse
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human
  • Ikbkb protein, mouse
  • Ikbke protein, mouse