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 Blood, 1 July 2007, Vol. 110, No. 1, pp. 259-266.
Prepublished online as a Blood First Edition Paper on March 15, 2007; DOI 10.1182/blood-2006-10-055194.

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IMMUNOBIOLOGY

Dok-3 plays a nonredundant role in negative regulation of B-cell activation

Chee-Hoe Ng1, Shengli Xu1, and Kong-Peng Lam1,2

1 Laboratory of Molecular and Cellular Immunology, Biomedical Sciences Institutes, Agency for Science, Technology and Research (A*STAR) and 2 Singapore Immunology Network, Singapore

p62dok and Dok-3 are members of the Dok family of adaptors found in B cells, with the former cloned as a substrate of the p210bcr/abl oncoprotein in Ph + chronic myelogenous leukemia. A role for p62dok in Fc{gamma}RIIB–mediated negative regulation of B-cell proliferation had been established previously. Here, we generated Dok-3–/– mice to assess the function of Dok-3 in B cells. Mice lacking Dok-3 have normal B-cell development but possess higher level of IgM antibodies in their sera. In comparison to wild-type mice, Dok-3–/– mice mounted significantly enhanced humoral immune responses to T cell–independent type I and II antigens. Dok-3–deficient B cells hyperproliferated, exhibited elevated level of calcium signaling as well as enhanced activation of NF-{kappa}B, JNK, and p38MAPK in response to B-cell receptor (BCR) engagement. In the absence of Dok-3, the localization of the inhibitory phosphatase SHIP-1 to the plasma membrane is intact while its phosphorylation is compromised, suggesting that Dok-3 could function to facilitate or sustain the activation of SHIP-1. The phenotype and responses of Dok-3–/– mice and B cells could be differentiated from those of the Dok-1–/– counterparts. Hence, we propose that Dok-3 plays a distinct and nonredundant role in the negative regulation of BCR signaling.


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Related Article in Blood Online:

Important port for SHIP-1 at Dok-3
Kerry S. Campbell
Blood 2007 110: 3-4. [Full Text] [PDF]



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