Abstract:
:The fact that the Xid mutation of Btk impairs the ability of pleckstrin homology domain of Btk to bind phosphatidylinositol-(3,4,5)-trisphosphate, a product of class IA phosphoinositide-3 kinases (PI3Ks), has been considered strong evidence for the hypothesis that Btk functions downstream of PI3Ks. We demonstrate here that the Xid mutation renders the Btk protein unstable. Furthermore, class IA PI3K- and Btk-deficient mice show different phenotypes in B-cell development, collectively indicating that PI3Ks and Btk differentially function in BCR signal transduction. Nevertheless, both PI3K and Btk are required for the activation of NF-kappaB, a critical transcription factor family for B-cell development and function. We demonstrate that PI3Ks maintain the expression of NF-kappaB proteins, whereas Btk is known to be essential for IkappaB degradation and the translocation of NF-kappaB to the nucleus. The loss of PI3K activity results in marked reduction of c-Rel and to a lesser extent RelA expression. The lentivirus-mediated introduction of c-Rel corrects both developmental and proliferative defects in response to BCR stimulation in class IA PI3K-deficient B cells. These results show that the PI3K-mediated control of c-Rel expression is essential for B-cell functions.
journal_name
Bloodjournal_title
Bloodauthors
Matsuda S,Mikami Y,Ohtani M,Fujiwara M,Hirata Y,Minowa A,Terauchi Y,Kadowaki T,Koyasu Sdoi
10.1182/blood-2008-06-163725subject
Has Abstractpub_date
2009-01-29 00:00:00pages
1037-44issue
5eissn
0006-4971issn
1528-0020pii
blood-2008-06-163725journal_volume
113pub_type
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