BAFF activates Erk1/2 promoting cell proliferation and survival by Ca2+-CaMKII-dependent inhibition of PP2A in normal and neoplastic B-lymphoid cells

Abstract

B-cell activating factor (BAFF) is involved in not only the physiology of normal B cells, but also the pathophysiology of aggressive B cells related to malignant and autoimmune diseases. However, how excessive BAFF promotes aggressive B-cell proliferation and survival is not well understood. Here we show that excessive human soluble BAFF (hsBAFF) enhanced cell proliferation and survival in normal and B-lymphoid (Raji) cells, which was associated with suppression of PP2A, resulting in activation of Erk1/2. This is supported by the findings that pretreatment with U0126 or PD98059, expression of dominant negative MKK1, or overexpression of PP2A prevented hsBAFF-induced activation of Erk1/2 and cell proliferation/viability in the cells. It appears that hsBAFF-mediated PP2A-Erk1/2 pathway and B-cell proliferation/viability was Ca2+-dependent, as pretreatment with BAPTA/AM, EGTA or 2-APB significantly attenuated these events. Furthermore, we found that inhibiting CaMKII with KN93 or silencing CaMKII also attenuated hsBAFF-mediated PP2A-Erk1/2 signaling and B-cell proliferation/viability. The results indicate that BAFF activates Erk1/2, in part through Ca2+-CaMKII-dependent inhibition of PP2A, increasing cell proliferation/viability in normal and neoplastic B-lymphoid cells. Our data suggest that inhibitors of CaMKII and Erk1/2, activator of PP2A or manipulation of intracellular Ca2+ may be exploited for prevention of excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.

Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells

“…PP2A also negatively regulates Erk1/2 pathway through dephosphorylation of the Erk1/2 protein [25]. We have uncovered that hsBAFF activates Erk1/2, in part via inhibition of PP2A, in normal and neoplastic B-lymphoid cells [34]. Putting all data together, we postulated that a cross-talk may occur between mTOR and PP2A-Erk1/2 pathways in B cells in response to BAFF, i.e., BAFF stimulation of mTOR may repress PP2A, resulting in activation of Erk1/2, which may be prevented by rapamycin.…”

“…Our recent studies have shown that excessive hsBAFF promotes proliferation and survival in B lymphocytes via activation of mTOR and Erk1/2 signaling network [24,34]. By inhibiting activation of mTOR pathway, rapamycin can effectively prevent hsBAFF-induced proliferation/viability in primary mouse B lymphocytes [24].…”

“…Our recent studies have demonstrated that excess BAFF inhibits PP2A activity, thereby activating Erk1/2 signaling and promoting B-cell proliferation and survival [34]. Therefore, here we tested whether rapamycin exerts the d The percentages of live (Q3), early apoptotic (Q4), late apoptotic (Q2) and necrotic cells (Q1) were determined by FACS using annexin-V-FITC/PI staining.…”

“…i elevation activates Erk1/2 pathway contributing to proliferation and survival of primary mouse B lymphocytes [33]. We have also pinpointed that excessive hsBAFF activates Erk1/2 promoting cell proliferation and survival by inhibition of PP2A in normal and neoplastic B-lymphoid cells [34]. It has been described that mTOR mediates phosphorylation of S6K1 and 4E-BP1 by inhibiting PP2A [35].…”

Baicalin alleviates ischemia-induced memory impairment by inhibiting the phosphorylation of CaMKII in hippocampus

“…For example, CaMKII activation by cGMP-dependent protein kinase (PKG) occurred in an ERK-1/2-dependent manner, which indicated that ERK-1/2 is upstream of CaMKII . Inhibiting CaMKII with KN-93 or silencing CaMKII attenuated activating factor-induced activation of ERK-1/2 in human soluble B-cells, which suggested that ERK-1/2 activation was in part through CaMKII-dependence and ERK-1/2 was downstream of CaMKII (Liang et al, 2014). So it is 4 possible that CaMKII is another signaling mechanism underlying the action of baicalin on global cerebral ischemic impairment.…”