Bex1, a novel interactor of the p75 neurotrophin receptor, links neurotrophin signaling to the cell cycle

Abstract

A screening for intracellular interactors of the p75 neurotrophin receptor (p75NTR) identified brain‐expressed X‐linked 1 (Bex1), a small adaptor‐like protein of unknown function. Bex1 levels oscillated during the cell cycle, and preventing the normal cycling and downregulation of Bex1 in PC12 cells sustained cell proliferation under conditions of growth arrest, and inhibited neuronal differentiation in response to nerve growth factor (NGF). Neuronal differentiation of precursors isolated from the brain subventricular zone was also reduced by ectopic Bex1. In PC12 cells, Bex1 overexpression inhibited the induction of NF‐κB activity by NGF without affecting activation of Erk1/2 and AKT, while Bex1 knockdown accelerated neuronal differentiation and potentiated NF‐κB activity in response to NGF. Bex1 competed with RIP2 for binding to the p75NTR intracellular domain, and elevating RIP2 levels restored the ability of cells overexpressing Bex1 to differentiate in response to NGF. Together, these data establish Bex1 as a novel link between neurotrophin signaling, the cell cycle, and neuronal differentiation, and suggest that Bex1 may function by coordinating internal cellular states with the ability of cells to respond to external signals.

Bex1 knock out mice show altered skeletal muscle regeneration

“…3). This finding is consistent with the report that Bex1 protein is highly expressed in developing muscle, where it is localized in somatic mesenchyme [14]. We suggest that the lack of Bex1 in mice may alter normal development of muscle and lead to a reduction in exercise performance.…”

“…There are several reasons why a Bex1 and CaM interaction during skeletal muscle regeneration would be important to elucidate. Expression of Bex1 is transiently elevated at the end of the proliferation state of skeletal muscle regeneration [9,10] and several studies implicate the Bex1 protein in cell growth and differentiation [13,14]. On the other hand, CaM is a ubiquitous Ca2+ binding protein, but one that is poorly studied in muscle regeneration.…”

Brain-Expressed X-linked (BEX) proteins in human cancers

“…TrkA and BEX3 co-expressed in embryonic rat dorsal root ganglia (DRG) neurons and also form complex further suggesting a possible role BEX3 in neuron development. Like BEX3, BEX1 was also found to be associated with p75NTR in PC12 cells and the interaction was independent of NGF stimulation [16].…”

“…Furthermore, overexpression of BEX1 in PC12 cells was associated with reduced NFκB activity in response to NGF as well as elevated differentiation capacity, while knockdown of BEX1 potentiated NFκB activity in response to NGF [16]. Therefore, it has been suggested that both BEX1 and BEX3 interact with p75NTR and regulate NGF-induced apoptosis and differentiation in neural tissues through NF-B (Fig.…”

“…Other serine/threonine protein kinases can also phosphorylate BEX proteins. A more recent study identified a serine phosphorylation site in mouse BEX1 which is phosphorylated by the serine/threonine protein kinase AKT [16].…”