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J. Biol. Chem., Vol. 276, Issue 23, 20055-20063, June 8, 2001
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From the Institute of Molecular and Cell Biology, 30 Medical Drive,
Singapore 117609, Singapore
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
The Adaptor Protein BLNK Is Required for B Cell Antigen
Receptor-induced Activation of Nuclear Factor-
B and Cell Cycle
Entry and Survival of B Lymphocytes*
,,
/ 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-xL, 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)-
B that is known to regulate genes
involved in cell proliferation and survival. The inability to activate
NF-B in BCR-stimulated BLNK/ B cells is
due to a failure to induce the degradation of the inhibitory B
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)-
2
has also been demonstrated to be essential for NF-B activation.
Since BLNK has been shown separately to interact with both Btk and
PLC-2, our finding of normal Btk but impaired PLC-2 activation in
BCR-stimulated BLNK/ B cells strongly
suggests that BLNK orchestrates the formation of a Btk-PLC-2
signaling axis that regulates NF-B activation. Taken together, the
NF-B 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-2/ mice.
*
This work was supported by grants from the National Science
and Technology Board of Singapore.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
These authors contributed equally to this work.
§
To whom correspondence should be addressed. Tel.:
65-874-3784; Fax: 65-779 -1117; E-mail:
mcblamkp@imcb.nus.edu.sg.
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