PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling.
NF-kappa B signaling is required for the maintenance of normal B lymphocytes, whereas dysregulated NF-kappa B activation contributes to B cell lymphomas. The events that regulate NF-kappa B signaling in B lymphocytes are poorly defined. Here, we demonstrate that PKC-beta is specifically required for B cell receptor (BCR)-mediated NF-kappa B activation. B cells from protein kinase C-beta (PKC-beta)-deficient mice failed to recruit the I kappa B kinase (IKK) complex into lipid rafts, activate IKK, degrade I kappa B or up-regulate NF-kappa B-dependent survival signals. Inhibition of PKC-beta promoted cell death in B lymphomas characterized by exaggerated NF-kappa B activity. Together, these data define an essential role for PKC-beta in BCR survival signaling and highlight PKC-beta as a key therapeutic target for B-lineage malignancies.
The Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Thomas T
TT
Su
Beichu
B
Guo
Yuko
Y
Kawakami
Karen
K
Sommer
Keun
K
Chae
Lisa A
LA
Humphries
Roberta M
RM
Kato
Shin
S
Kang
Lisa
L
Patrone
Randolph
R
Wall
Michael
M
Teitell
Michael
M
Leitges
Toshiaki
T
Kawakami
David J
DJ
Rawlings
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000276:immunology; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology; D008301:Maleimides / Q000494:pharmacology; D008698:Mesylates / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000276:immunology*; D064546:Protein Kinase C beta; D017346:Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
C434605:5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D008698:Mesylates; D016328:NF-kappa B; D011758:Pyrroles; D011947:Receptors, Antigen, B-Cell; C071924:Ro 31-8425; 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