CD22 cross-linking generates B-cell antigen receptor-independent signals that activate the JNK/SAPK signaling cascade

CD22 is a B-cell-specific adhesion molecule that modulates BCR-mediated sig nal transduction. Ligation of human CD22 with monoclonal antibodies (MoAbs) that block the ligand binding site triggers rapid tyrosine phosphorylation of CD22 and primary B-cell proliferation. Because extracellular signal-reg ulated kinases (ERKs) couple upstream signaling pathways to gene activation and are activated by B-cell antigen receptor (BCR) signaling, we examined whether CD22 ligation also activated ERKs and/or modified BCR-induced ERK a ctivation. Ligation of CD22 on either primary B cells or B-cell lines faile d to significantly activate the mitogen activated protein kinase (MAPK) ERK -2, but did activate the stress-activated protein kinases (SAPKs; c-jun NH2 -terminal kinases or JNKs). In contrast, BCR ligation resulted in ERK-5 act ivation without significant SAPK activation. Concurrent ligation of CD22 an d BCR enhanced BCR-mediated ERK-2 activation without appreciably modulating CD22-induced SAPK activation. Consistent with its induction of SAPK activi ty, there was a marked increase in nuclear extracts of activator protein-1 (AP-1) and c-jun levels within 2 hours of exposure of primary B cells to th e CD22 MoAb. Despite their differences in ERK activation, both CD22 and BCR ligation triggered several Burkitt lymphoma cell lines to undergo apoptosi s, and the 2 stimuli together induced greater cell death than either signal alone. The pro-apoptotic effects were CD22-blocking MoAb-specific and dose -dependent. Examination of expression levels of Bcl-2 protoncogene family m embers (Bcl-2, Bcl-x(L), Mcl-1, and Bar) showed a downregulation of Bcl-x(L ) and Mcl-1 after CD22 ligation. This study provides a plausible mechanism to explain how CD22 and BCR signaling can costimulate B-cell proliferation and induce apoptosis in Burkitt lymphoma cell lines.