PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization.
Mutations in Bruton's tyrosine kinase (Btk) result in X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. While targeted disruption of the protein kinase C-beta (PKCbeta) gene in mice results in an immunodeficiency similar to xid, the overall tyrosine phosphorylation of Btk is significantly enhanced in PKCbeta-deficient B cells. We provide direct evidence that PKCbeta acts as a feedback loop inhibitor of Btk activation. Inhibition of PKCbeta results in a dramatic increase in B-cell receptor (BCR)-mediated Ca2+ signaling. We identified a highly conserved PKCbeta serine phosphorylation site in a short linker within the Tec homology domain of Btk. Mutation of this phosphorylation site led to enhanced tyrosine phosphorylation and membrane association of Btk, and augmented BCR and FcepsilonRI-mediated signaling in B and mast cells, respectively. These findings provide a novel mechanism whereby reversible translocation of Btk/Tec kinases regulates the threshold for immunoreceptor signaling and thereby modulates lymphocyte activation.
Kang
S W
SW
Department of Pediatrics, University of California, Los Angeles, CA 90095-1752, USA.
Wahl
M I
MI
Chu
J
J
Kitaura
J
J
Kawakami
Y
Y
Kato
R M
RM
Tabuchi
R
R
Tarakhovsky
A
A
Kawakami
T
T
Turck
C W
CW
Witte
O N
ON
Rawlings
D J
DJ
D016475:3T3 Cells; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology; D020013:Calcium Signaling / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005246:Feedback; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology*; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010449:Peptide Mapping; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D064546:Protein Kinase C beta; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D017455:Receptors, IgE / Q000502:physiology
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011947:Receptors, Antigen, B-Cell; D017455:Receptors, IgE; D010768:Phosphoserine; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D011493:Protein Kinase C; D064546:Protein Kinase C beta