Nature Immunology
2, 939 - 946 (2001)
Published online: 1 October 2001; | doi:10.1038/ni1001-939
Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding proteinWeimin Liu1, Ileana Quinto1, 2, Xueni Chen1, Camillo Palmieri1, Ronald L. Rabin3, Owen M. Schwartz4, David L Nelson5
& Giuseppe Scala1, 21
Department of Clinical and Experimental Medicine, Medical School, University of Catanzaro, 88100 Catanzaro, Italy. 2
Department of Biochemistry and Biomedical Technology, Medical School, University 'Federico II', 80131 Naples, Italy. 3
Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1374, USA. 4
Biological Imaging Facility, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD 20892-1374, USA. 5
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1374, USA.
Correspondence should be addressed to Giuseppe Scala scala@dbbm.unina.itBruton'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- B−driven transcription. These results define a potential mechanism for the regulation of Btk function in B cells.
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