Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein.
Bruton's tyrosine kinase (Btk) is required for human and mouse B cell development. Btk deficiency causes X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency in mice. Unlike Src proteins, Btk lacks a negative regulatory domain at the COOH terminus and may rely on cytoplasmic Btk-binding proteins to regulates its kinase activity by trans-inhibitor mechanisms. Consistent with this possibility, IBtk, which we identified as an inhibitor of Btk, bound to the PH domain of Btk. IBtk downregulated Btk kinase activity, Btk-mediated calcium mobilization and nuclear factor-kappaB-driven transcription. These results define a potential mechanism for the regulation of Btk function in B cells.
Liu
W
W
Department of Clinical and Experimental Medicine, Medical School, University of Catanzaro, 88100 Catanzaro, Italy.
Quinto
I
I
Chen
X
X
Palmieri
C
C
Rabin
R L
RL
Schwartz
O M
OM
Nelson
D L
DL
Scala
G
G
D048868:Adaptor Proteins, Signal Transducing; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D014018:Tissue Distribution; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C437966:IBtk protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D002118:Calcium