| Research Abstract |
In the original proposal, we planed to search for the ligand for CD45. Recent studies demonstrated that CD45 catalytic activity is regulated by dimerization and that dimerization may be dependent on the extracellular domain of CD45 such that CD45RO is more susceptible to dimerization than CD45RABC. These findings suggest that ligands acting in trans may not be required for the regulation of CD45 activity. We therefore pursued to elucidate the signaling pathways regulated by CD45.
(1) Regulation ofmitogen-activated protein kinases (MAPKs) by CD45: We previously showed that CD45 exerts differential effects on B cell receptor (BCR) signaling in two B cell lines, WEHI-231 and BAL-17, which represent different inaturational stages. In this study, we examined the contribution made by CD45 to BCR-induced activation of MAPK family members. We found that CD45 negatively regulated BCR-induced c-Jun NH_2-terminal kinase (INK) and p38 activation in immature WEHI-231 cells, whereas in mature BAL-17 cells, CD45 positively regulated JNK and p38 activation and negatively regulated extracellular signal-regulated kinase (ERK) activity. Furthermore, cooperative action of JNK and p38 dictated BCR-induced inhibition of growth. Thus, CD45 appears to differentially regulate BCR-induced activation of MAPK members, and can exert opposing effects on JNK and p38 in different cellular milieus, controlling the B cell fate.
(2) Regulation of CD40-mediated signaling pathways by CD45: In BAL-17 cells, CD40 ligation did not rescue BCR-induced growth inhibition but itself inhibited proliferation. This effect was dependent on CD45. Furthermore, CD40-induced inhibition of proliferation was controlled by JNK and p38, the activity of which was also regulated by CD45. However, CD40-mediated induction of cell surface molecules was not regulated by CD45. Thus, these results suggest that CD45 exerts a decisive effect on selective sets of CD40-mediated signaling pathways, dictating B cell fate.
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