PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction.
Phosphoinositide-3 kinase (PI3K) is thought to activate the tyrosine kinase Btk. However, through analysis of PI3K-/- and Btk-/- mice, B cell antigen receptor (BCR)-induced activation of Btk in mouse B cells was found to be unaffected by PI3K inhibitors or by a lack of PI3K. Consistent with this observation, PI3K-/- Btk-/- double-deficient mice had more severe defects than either single-mutant mouse. NF-kappaB activation along with Bcl-xL and cyclin D2 induction were severely blocked in both PI3K-/- and Btk-/- single-deficient B cells. Transgenic expression of Bcl-xL restored the development and BCR-induced proliferation of B cells in PI3K-/- mice. Our results indicate that PI3K and Btk have unique roles in proximal BCR signaling and that they have a common target further downstream in the activation of NF-kappaB.
Suzuki
Harumi
H
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Matsuda
Satoshi
S
Terauchi
Yasuo
Y
Fujiwara
Mari
M
Ohteki
Toshiaki
T
Asano
Tomoichiro
T
Behrens
Timothy W
TW
Kouro
Taku
T
Takatsu
Kiyoshi
K
Kadowaki
Takashi
T
Koyasu
Shigeo
S
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D051020:bcl-X Protein
D000077329:Agammaglobulinaemia Tyrosine Kinase; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D051020:bcl-X Protein; C494812:Bcl2l1 protein, mouse