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Molecular and Cellular Biology, April 2000, p. 2743-2754, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Dok-3, a Novel Adapter Molecule Involved in the Negative Regulation of Immunoreceptor Signaling

Serge Lemay,1 Dominique Davidson,1,2 Sylvain Latour,1,2 and André Veillette1,2,3,4,5,*

McGill Cancer Centre1 and Departments of Biochemistry,3 Oncology,4 and Medicine,5 McGill University, Montréal, Québec, Canada H3G 1Y6, and Laboratory of Molecular Oncology, IRCM, Montréal, Québec, Canada H2W 1R72

Received 21 October 1999/Returned for modification 30 November 1999/Accepted 20 January 2000

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.

* Corresponding author. Mailing address: Laboratory of Molecular Oncology, IRCM, 110 Pine Ave. West, Montréal, Québec, Canada H2W 1R7. Phone: (514) 987-5561. Fax: (514) 987-5562. E-mail: veillea{at}ircm.qc.ca.

Molecular and Cellular Biology, April 2000, p. 2743-2754, Vol. 20, No. 8
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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