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

Sci Signal. 2021 May 11;14(682):eabc1648. doi: 10.1126/scisignal.abc1648.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology*
  • Cell Differentiation
  • Extracellular Signal-Regulated MAP Kinases* / genetics
  • Extracellular Signal-Regulated MAP Kinases* / metabolism
  • Mice
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Plasma Cells / cytology*
  • Proto-Oncogene Proteins c-raf* / genetics
  • Proto-Oncogene Proteins c-raf* / metabolism

Substances

  • Proto-Oncogene Proteins c-raf
  • Extracellular Signal-Regulated MAP Kinases