Dabrafenib Promotes Schwann Cell Differentiation by Inhibition of the MEK-ERK Pathway.

Kyuhee Park,Hwantae Park,Yoonkyoung Shin,Gyeongbeen Lee,Yongmun Choi

doi:10.3390/molecules26082141

Abstract

Schwann cell differentiation involves a dynamic interaction of signaling cascades. However, much remains to be elucidated regarding the function of signaling molecules that differ depending on the context in which the molecules are engaged. Here, we identified a small molecule, dabrafenib, which promotes Schwann cell differentiation in vitro and exploited this compound as a pharmacological tool to understand the molecular mechanisms regulating Schwann cell differentiation. The results indicated that dabrafenib inhibited ERK phosphorylation and enhanced ErbB2 autophosphorylation and Akt phosphorylation, and the effects of dabrafenib on ErbB2 and Akt phosphorylation were phenocopied by pharmacological inhibition of the MEK-ERK signaling pathway. However, the small molecule inhibitors of MEK and ERK had no effect on the expression of Oct6 and EGR2, which are key transcription factors that drive Schwann cell differentiation. In addition, pharmacological inhibition of phosphatidylinositol-3-kinase (PI3K) almost completely interfered with dabrafenib-induced Schwann cell differentiation. These results suggest that the ErbB2-PI3K-Akt axis is required for the induction of Schwann cell differentiation by dabrafenib in vitro. Although additional molecules targeted by dabrafenib remain to be identified, our data provides insights into the crosstalk that exists between the MEK-ERK signaling pathway and the PI3K-Akt axis in Schwann cell differentiation.

Highlights

In the adult peripheral nervous system (PNS), mature Schwann cells wrap nerve fibers similar to the oligodendrocytes in the central nervous system [1]
The expression of c-Jun is downregulated as Schwann cells undergo redifferentiation, which is induced by axonal signals including the interaction of neuregulin 1 (Nrg1) type III in the regenerated axons and its receptors (ErbB2/3) [6,7]
Our efforts to discover such small molecules led to the identification of dabrafenib, and by exploiting dabrafenib as a pharmacological tool, we provide further evidence regarding the role of the MEK-ERK pathway in negatively regulating Schwann cell differentiation in vitro

Summary

Introduction

In the adult peripheral nervous system (PNS), mature Schwann cells wrap nerve fibers similar to the oligodendrocytes in the central nervous system [1]. Unlike oligodendrocytes, Schwann cells can support axon regeneration upon nerve injury in the PNS This is primarily attributable to Schwann cell plasticity, which is described as the intrinsic capacity of mature Schwann cells to dedifferentiate into proliferative progenitorlike cells upon axon degeneration [2]. Recent years have seen some progress in understanding the molecular mechanisms underlying Schwann cell plasticity, and a range of signaling molecules involved in the dedifferentiation and redifferentiation of Schwann cells have been identified [4]. Among these is the c-Jun transcription factor, which is highly upregulated in Schwann cells following nerve injury and functions to induce a demyelination program [5]. Genetic and biochemical studies have uncovered intrinsic mechanisms linking axonal signals to Schwann cell differentiation, the activity and function of signaling molecules that differ depending on developmental stages of Schwann cells need to be determined [8]

Methods

Results

Conclusion