Research ArticleImmunology

ERK phosphorylation is RAF independent in naïve and activated B cells but RAF dependent in plasma cell differentiation

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Science Signaling  11 May 2021:
Vol. 14, Issue 682, eabc1648
DOI: 10.1126/scisignal.abc1648

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RAFs not always required

The kinase activity of ERK is necessary at many stages during B cell differentiation. In most cell types, ERK phosphorylation and activation usually requires RAF family kinases. Scheffler et al. found that mice lacking both B-Raf and Raf-1 had reduced numbers of pre-B and immature B cells in the bone marrow and mature B cells in the periphery, and they generated fewer plasma cells upon immunization. Although mature B cells isolated from the mutant mice exhibited normal or even increased ERK activation under basal conditions and upon stimulation, they showed reduced ERK phosphorylation at the onset of plasma cell differentiation. RAFs are mainly required for the transition of pro-B cells to pre-B cells and for the differentiation of activated B cells into antibody-secreting plasma cells.

Abstract

Members of the RAF family of serine-threonine kinases are intermediates in the mitogen-activated protein kinase and extracellular signal–regulated kinase (MAPK-ERK) signaling pathway, which controls key differentiation processes in B cells. By analyzing mice with B cell–specific deletion of Raf1, Braf, or both, we showed that Raf-1 and B-Raf acted together in mediating the positive selection of pre-B and transitional B cells as well as in initiating plasma cell differentiation. However, genetic or chemical inactivation of RAFs led to increased ERK phosphorylation in mature B cells. ERK activation in the absence of Raf-1 and B-Raf was mediated by multiple RAF-independent pathways, with phosphoinositide 3-kinase (PI3K) playing an important role. Furthermore, we found that ERK phosphorylation strongly increased during the transition from activated B cells to pre-plasmablasts. This increase in ERK phosphorylation did not occur in B cells lacking both Raf-1 and B-Raf, which most likely explains the partial block of plasma cell differentiation in mice lacking both RAFs. Collectively, our data indicate that B-Raf and Raf-1 are not necessary to mediate ERK phosphorylation in naïve or activated B cells but are essential for mediating the marked increase in ERK phosphorylation during the transition from activated B cells to pre-plasmablasts.

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