Elucidating the role of Dok-3 in B cell receptor signaling using gene knockout mice

Abstract

Dok-3 is a negative regulator of B cell receptor signaling. To date, the physiological function of Dok-3 is still unclear. We have generated the Dok-3-/- mice. Dok-3-/- mice have normal B cell population in the central and peripheral immune organs; exhibit elevated basal serum IgM but normal IgG1, IgG2a, IgG2b and IgG3; hyper-responsive towards T-independent antigens but showed comparable primary and secondary responses when challenged by a T-dependent antigen. Dok-3-/- B cells also hyper-proliferated and exhibited elevated magnitude of calcium flux in response to B cell receptor stimulation. We found that in Dok-3-/- B cells, SHIP1 was not activated optimally upon BCR stimulation, with reduced phosphorylation at tyrosine 1020. Dok-3-/- B cells also showed enhanced phosphorylation of JNK and p38; exhibited increased IkappaBalpha degradation accompanied by enhanced NFkappaB DNA binding. As such, all experiments pointed towards Dok-3 as a negative regulator of B cell receptor signaling.