Dok-3 plays a nonredundant role in negative regulation of B-cell activation.
p62(dok) and Dok-3 are members of the Dok family of adaptors found in B cells, with the former cloned as a substrate of the p210(bcr/abl) oncoprotein in Ph + chronic myelogenous leukemia. A role for p62(dok) in FcgammaRIIB-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-kappaB, 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.
Ng
Chee-Hoe
CH
Laboratory of Molecular and Cellular Immunology, Biomedical Sciences Institutes, Agency for Science, Technology and Research, Proteos, Singapore.
Xu
Shengli
S
Lam
Kong-Peng
KP
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D007075:Immunoglobulin M / Q000097:blood; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C406768:Dok3 protein, mouse; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6