Dok-3, a novel adapter molecule involved in the negative regulation of immunoreceptor signaling

S Lemay, D Davidson, S Latour… - Molecular and cellular …, 2000 - Am Soc Microbiol
S Lemay, D Davidson, S Latour, A Veillette
Molecular and cellular biology, 2000Am Soc Microbiol
Adapters are typically viewed as molecules coordinating the recruitment of positive effectors
of cell signaling. Herein, we report the identification of Dok-3, a novel adapter molecule
belonging to the Dok family. Our studies show that Dok-3 is highly expressed in several
hemopoietic cell types, including B cells and macrophages. It undergoes rapid tyrosine
phosphorylation in response to immunoreceptor-mediated cellular activation, seemingly as
a result of the action of Src family kinases. This phosphorylation induces the binding of Dok …
Abstract
Adapters are typically viewed as molecules coordinating the recruitment of positive effectors of cell signaling. Herein, we report the identification of Dok-3, a novel adapter molecule belonging to the Dok family. Our studies show that Dok-3 is highly expressed in several hemopoietic cell types, including B cells and macrophages. It undergoes rapid tyrosine phosphorylation in response to immunoreceptor-mediated cellular activation, seemingly as a result of the action of Src family kinases. This phosphorylation induces the binding of Dok-3 to at least two inhibitory molecules, the 5′ inositol phosphatase SHIP and the protein tyrosine kinase Csk. We also demonstrate that augmented expression of wild-type Dok-3 in a B-cell line results in an inhibition of immunoreceptor-mediated nuclear factor of activated T-cells (NFAT) activation and cytokine release, while introduction of a Dok-3 mutant with impaired ability to associate with SHIP and Csk enhances B-cell responsiveness. Taken together, these results indicate that Dok-3 is an adapter involved in the recruitment of inhibitory molecules and that it may play a significant role in the negative regulation of immunoreceptor signaling in hemopoietic cells such as B cells and macrophages.
American Society for Microbiology