Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase.
The generation and maintenance of B lymphocytes is controlled by biochemical signals transmitted by the B cell antigen receptor(BCR) complex. These signals are transduced by multiple cytoplasmic protein tyrosine kinases (PTKs) including Lyn, Syk, and Bruton's tyrosine kinase (BTK). Upon BCR engagement, these PTKs activate downstream effectors, including transcription factors that modulate gene expression. In turn, activation of downstream effectors is critical for B cell survival, cell cycle progression, and antibody production. Our studies focus on the role of BTK in these biological responses. We have discovered that BTK is required for activation of the BCR-responsive transcription factor, NF-kappaB. Furthermore, BTK-dependent activation of NF-kappaB is essential for reprogramming the expression of genes that control B cell survival and proliferation. The biochemical mechanisms by which BTK regulates signaling components that activate NF-kappaB, and the identification of BTK-responsive genes are under investigation. Elucidation of these regulatory mechanisms is expected to reveal new therapeutic targets for B cell pathologies involving defects in BTK, including X-linked agammaglobulinemia (XLA).
Khan
W N
WN
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-5632, USA. Khanwn@ctrvax.vanderbilt.edu
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology*; D002453:Cell Cycle; D002454:Cell Differentiation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018448:Models, Immunological; D016328:NF-kappa B / Q000502:physiology; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000502:physiology; D014960:X Chromosome / Q000235:genetics; D051020:bcl-X Protein; D019061:src-Family Kinases / Q000502:physiology
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D007527:Isoenzymes; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D051020:bcl-X Protein; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D019061:src-Family Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma