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Molecular and Cellular Biology, March 2004, p. 2332-2343, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2332-2343.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Inhibition of the Jun N-Terminal Protein Kinase Pathway by SHIP-1, a Lipid Phosphatase That Interacts with the Adaptor Molecule Dok-3

Jeffrey D. Robson,1,2 Dominique Davidson,1 and André Veillette1,2,3,4,5*

Laboratory of Molecular Oncology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada H2W 1R7,1 Departments of Biochemistry,2 Microbiology and Immunology,3 Medicine, McGill University, Montreal, Quebec, Canada H3G 1Y6,4 Department of Medicine, University of Montreal, Montreal, Quebec, Canada H3C 3J75

Received 22 October 2003/ Returned for modification 6 December 2003/ Accepted 11 December 2003

Dok-3 is a Dok-related adaptor expressed in B cells and macrophages. Previously, we reported that Dok-3 is an inhibitor of B-cell activation in A20 B cells and that it associates with SHIP-1, a 5' inositol-specific lipid phosphatase, as well as Csk, a negative regulator of Src kinases. Here, we demonstrate that Dok-3 suppresses B-cell activation by way of its interaction with SHIP-1, rather than Csk. Our biochemical analyses showed that the Dok-3-SHIP-1 complex acts by selectively inhibiting the B-cell receptor (BCR)-evoked activation of the Jun N-terminal protein kinase (JNK) cascade without affecting overall protein tyrosine phosphorylation or activation of previously described SHIP-1 targets like Btk and Akt/PKB. Studies of B cells derived from SHIP-1-deficient mice showed that BCR-triggered activation of JNK is enhanced in the absence of SHIP-1, implying that the Dok-3-SHIP-1 complex (or a related mechanism) is a physiological negative regulator of the JNK cascade in normal B cells. Together, these data elucidate the mechanism by which Dok-3 inhibits B-cell activation. Furthermore, they provide evidence that SHIP-1 can be a negative regulator of JNK signaling in B cells.

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

Molecular and Cellular Biology, March 2004, p. 2332-2343, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2332-2343.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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