Submitted October 30, 2006
Accepted March 13, 2007
Dok-3 plays a non-redundant role in negative regulation of B cell activation
Chee-Hoe Ng, Shengli Xu, and Kong-Peng Lam*
Laboratory of Molecular and Cellular Immunology, Biomedical Sciences Institutes, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
* Corresponding author; email: mcblamkp{at}imcb.a-star.edu.sg.
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 FcR
IIB-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 wildtype mice, Dok-3-/- mice mounted significantly enhanced humoral immune responses to T cell-independent type I and II antigens. Dok-3-deficient B cells hyper-proliferated, exhibited elevated level of calcium signaling as well as enhanced activation of NF-
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 non-redundant role in the negative regulation of BCR signaling.
