The adaptor protein BLNK is required for b cell antigen receptor-induced activation of nuclear factor-kappa B and cell cycle entry and survival of B lymphocytes.
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)-kappaB that is known to regulate genes involved in cell proliferation and survival. The inability to activate NF-kappaB in BCR-stimulated BLNK(-)/- B cells is due to a failure to induce the degradation of the inhibitory kappaB protein. In all these aspects, BLNK(-)/- B cells resemble xid B cells that have a mutation in Bruton's tyrosine kinase (Btk). Recently, phospholipase C (PLC)-gamma2 has also been demonstrated to be essential for NF-kappaB activation. Since BLNK has been shown separately to interact with both Btk and PLC-gamma2, our finding of normal Btk but impaired PLC-gamma2 activation in BCR-stimulated BLNK(-)/- B cells strongly suggests that BLNK orchestrates the formation of a Btk-PLC-gamma2 signaling axis that regulates NF-kappaB activation. Taken together, the NF-kappaB activation defect may be sufficient to explain the similar defects in BCR-induced B cell proliferation and T cell-independent immune responses in BLNK(-)/-, Btk(-)/-, and PLC-gamma2(-)/- mice.
Tan
J E
JE
Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Singapore.
Wong
S C
SC
Gan
S K
SK
Xu
S
S
Lam
K P
KP
D048868:Adaptor Proteins, Signal Transducing; D000077329:Agammaglobulinaemia Tyrosine Kinase; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism*; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; D007075:Immunoglobulin M; D007527:Isoenzymes; D016328:NF-kappa B; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D010738:Type C Phospholipases; D051966:Phospholipase C gamma