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B lymphocytes lacking the adaptor protein B cell linker (BLNK) do not proliferate in response to B cell antigen receptor (BCR) engagement. We demonstrate here that BCR-activated BLNK^−/− B cells fail to enter the cell cycle, and this is due to their inability to induce the expression of the cell cycle regulatory proteins such as cyclin D2 and cyclin-dependent kinase 4. BCR-stimulated BLNK^−/− B cells also do not up-regulate the cell survival protein Bcl-x_L, which may be necessary for the cells to complete the cell cycle. In addition, BLNK^−/− B cells exhibit a high rate of spontaneous apoptosis in culture. Examination of the various BCR-activated signaling pathways in mouse BLNK^−/− B cells reveals the intact activation of Akt and mitogen-activated protein kinases but the impaired activation of nuclear factor (NF)-κB that is known to regulate genes involved in cell proliferation and survival. The inability to activate NF-κB in …