Protein kinase C beta controls nuclear factor kappaB activation in B cells through selective regulation of the IkappaB kinase alpha.
Activation of the nuclear factor (NF)-kappaB transcription complex by signals derived from the surface expressed B cell antigen receptor controls B cell development, survival, and antigenic responses. Activation of NF-kappaB is critically dependent on serine phosphorylation of the IkappaB protein by the multi-component IkappaB kinase (IKK) containing two catalytic subunits (IKKalpha and IKKbeta) and one regulatory subunit (IKKgamma). Using mice deficient for protein kinase C beta (PKCbeta) we show an essential role of PKCbeta in the phosphorylation of IKKalpha and the subsequent activation of NF-kappaB in B cells. Defective IKKalpha phosphorylation correlates with impaired B cell antigen receptor-mediated induction of the pro-survival protein Bcl-xL. Lack of IKKalpha phosphorylation and defective NF-kappaB induction in the absence of PKCbeta explains the similarity in immunodeficiencies caused by PKCbeta or IKKalpha ablation in B cells. Furthermore, the well established functional cooperation between the protein tyrosine kinase Bruton's tyrosine kinase (Btk), which regulates the activity of NF-kappaB and PKCbeta, suggests PKCbeta as a likely serine/threonine kinase component of the Btk-dependent NF-kappaB activating signal transduction chain downstream of the BCR.
Saijo
Kaoru
K
Laboratory of Lymphocyte Signaling, Rockefeller University, New York, NY 10021, USA. saijok@mail.rockefeller.edu
Mecklenbräuker
Ingrid
I
Santana
Angela
A
Leitger
Michael
M
Schmedt
Christian
C
Tarakhovsky
Alexander
A
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism*; D051550:I-kappa B Kinase; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D007527:Isoenzymes; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D011493:Protein Kinase C; D064546:Protein Kinase C beta