Mechanism of Bruton's tyrosine kinase-mediated recruitment and regulation of TFII-I.
TFII-I is a ubiquitously expressed multifunctional transcription factor with broad biological roles in transcription and signal transduction in a variety of cell types. We and others have shown that TFII-I can interact physically and functionally with Bruton's tyrosine kinase (Btk), a hematopoietic non-receptor protein tyrosine kinase that is critical for ... B lymphocyte development. Although TFII-I-Btk interactions are impaired in B cells from X-linked immunodeficient mice, the precise molecular determinants governing TFII-I-Btk complex formation remain unknown. To this end, we have conducted a structural analysis of TFII-I-Btk interactions by using a panel of TFII-I mutants. These studies have revealed that a region within the N-terminal 90 amino acids of TFII-I, which includes a putative leucine zipper motif, is primarily responsible for its interaction with Btk. Mutations in the leucine zipper region itself were not sufficient to abrogate binding of TFII-I to Btk, suggesting that regions/residues outside the leucine zipper are responsible for such interactions. Because the first 90 amino acids of TFII-I are required for its dimerization, we propose that Btk tethers TFII-I to the cytoplasm by preventing its dimerization and its subsequent nuclear localization. We further examined the requirement of tyrosine phosphorylation for TFII-I-Btk complex formation. Our data showed that Src-dependent tyrosine phosphorylation sites in TFII-I are not targeted by Btk, suggesting that multiple kinases can independently target TFII-I via distinct signaling pathways. Our results provide a beginning step toward understanding the functional importance of the TFII-I-Btk pathway in B cell signaling and gene expression.
Mesh Terms:
Amino Acid Motifs, Amino Acids, Animals, B-Lymphocytes, Blotting, Western, COS Cells, Cell Nucleus, Cytoplasm, Dimerization, Fibroblasts, Gene Expression Regulation, Enzymologic, Genes, Reporter, Glutathione Transferase, Leucine, Luciferases, Mice, Microscopy, Fluorescence, Mutation, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Signal Transduction, Transcription Factors, TFII, Transfection, Tyrosine
Amino Acid Motifs, Amino Acids, Animals, B-Lymphocytes, Blotting, Western, COS Cells, Cell Nucleus, Cytoplasm, Dimerization, Fibroblasts, Gene Expression Regulation, Enzymologic, Genes, Reporter, Glutathione Transferase, Leucine, Luciferases, Mice, Microscopy, Fluorescence, Mutation, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Signal Transduction, Transcription Factors, TFII, Transfection, Tyrosine
J. Biol. Chem.
Date: Feb. 20, 2004
PubMed ID: 14623887
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