| RRC ID |
39615
|
| Author |
Petro JB, Rahman SM, Ballard DW, Khan WN.
|
| Title |
Bruton's tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement.
|
| Journal |
J Exp Med
|
| 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.
|
| Volume |
191(10)
|
| Pages |
1745-54
|
| Published |
2000-5-15
|
| DOI |
10.1084/jem.191.10.1745
|
| PMID |
10811867
|
| PMC |
PMC2193161
|
| MeSH |
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
|
| IF |
11.743
|
| Times Cited |
242
|
|
WOS Category
|
IMMUNOLOGY
MEDICINE, RESEARCH & EXPERIMENTAL
|
| Resource |
| Human and Animal Cells |
Btk^(-) DT40(RCB1468) |
