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Department of Immunology and Bacteriology, University of Glasgow, Glasgow, United Kingdom
One of the major unresolved questions in B cell biology is how the
B cell Ag receptor (BCR) differentially signals to transduce anergy,
apoptosis, proliferation, or differentiation during B cell maturation.
We now report that extracellularly regulated kinase-mitogen-activated
protein kinase (Erk-MAP kinase) can play dual roles in the regulation
of the cell fate of the immature B cell lymphoma, WEHI-231, depending
on the kinetics and context of Erk-MAP kinase activation. First, we
show that the BCR couples to an early (
2 h) Erk-MAP kinase signal
which activates a phospholipase A2 pathway that we have
previously shown to mediate collapse of mitochondrial membrane
potential, resulting in depletion of cellular ATP and cathepsin B
execution of apoptosis. Rescue of BCR-driven apoptosis by CD40
signaling desensitizes such early extracellularly regulated kinase
(Erk) signaling and hence uncouples the BCR from the apoptotic
mitochondrial phospholipase A2 pathway. A second role for
Erk-MAP kinase in promoting the growth and proliferation of WEHI-231
immature B cells is evidenced by data showing that proliferating and
CD40-stimulated WEHI-231 B cells exhibit a sustained cycling pattern
(8–48 h) of Erk activation that correlates with cell growth and
proliferation. This growth-promoting role for Erk signaling is
supported by three key pieces of evidence: 1) signaling via the BCR,
under conditions that induce growth arrest, completely abrogates
sustained Erk activation; 2) CD40-mediated rescue from growth arrest
correlates with restoration of cycling Erk activation; and 3) sustained
inhibition of Erk prevents CD40-mediated rescue of BCR-driven
growth arrest of WEHI-231 immature B cells. Erk-MAP kinase can
therefore induce diverse biological responses in WEHI-231 cells
depending on the context and kinetics of
activation.
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