Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion

Abstract

The pre-B cell receptor (pre-BCR) plays a crucial role in the development of immature B cells. Although certain aspects of proximal pre-BCR signaling have been studied, the intermediate signal transducers and the distal transcription modulators are poorly characterized. Here, we demonstrate that deletion of both Erk1 and Erk2 kinases was associated with defective pre-BCR-mediated cell expansion as well as a block in the transition of pro-B to pre-B cells. Phosphorylation of transcription factors Elk1 and CREB was mediated by Erk, and a dominant-negative mutation in the Erk-mediated phosphorylation sites of Elk1 or CREB suppressed pre-BCR-mediated cell expansion as well as expression of genes including Myc, which is involved in the cell-cycle progression. Together, our results identify a crucial role for Erk kinases in regulating B cell development by initiating transcriptional regulatory network and thereby pre-BCR-mediated cell expansion.