Regulation of Btk by Src family tyrosine kinases.
|Title||Regulation of Btk by Src family tyrosine kinases.|
|Publication Type||Journal Article|
|Year of Publication||1996|
|Authors||Afar DE, Park H, Howell BW, Rawlings DJ, Cooper J, Witte ON|
|Journal||Molecular and cellular biology|
|Date Published||1996 Jul|
|Keywords||Animals, Blotting, Western, Cell Line, Humans, Peptide Mapping, Phosphopeptides, Phosphorylation, Point Mutation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins pp60(c-src), Rats, Recombinant Proteins, Transfection|
Loss of function of Bruton's tyrosine kinase (Btk) results in X-linked immunodeficiencies characterized by a broad spectrum of signaling defects, including those dependent on Src family kinase-linked cell surface receptors. A gain-of-function mutant, Btk*, induces the growth of fibroblasts in soft agar and relieves the interleukin-5 dependence of a pre-B-cell line. To genetically define Btk signaling pathways, we used a strategy to either activate or inactivate Src family kinases in fibroblasts that express Btk*. The transformation potential of Btk* was dramatically increased by coexpression with a partly activated c-Src mutant (E-378 --> G). This synergy was further potentiated by deletion of the Btk Src homology 3 domain. Downregulation of Src family kinases by the C-terminal Src kinase (Csk) suppressed Btk* activation and biological potency. In contrast, kinase-inactive Csk (K-222 --> R), which functioned as a dominant negative molecule, synergized with Btk* in biological transformation. Activation of Btk* correlated with increased phosphotyrosine on transphosphorylation and autophosphorylation sites. These findings suggest that the Src and Btk kinase families form specific signaling units in tissues in which both are expressed.
|Alternate Journal||Mol. Cell. Biol.|