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

Autor: Hwan-Tae Park, Yongmun Choi, Gyeongbeen Lee, Kyuhee Park, Yoonkyoung Shin
Jazyk: angličtina
Rok vydání: 2021
Předmět:
MAPK/ERK pathway
Cell signaling
MAP Kinase Signaling System
Receptor
ErbB-2
Pharmaceutical Science
Schwann cell
Article
Analytical Chemistry
Rats
Sprague-Dawley
lcsh:QD241-441
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
ErbB2
lcsh:Organic chemistry
Oximes
Drug Discovery
medicine
Animals
Phosphorylation
Physical and Theoretical Chemistry
dabrafenib
Transcription factor
PI3K/AKT/mTOR pathway
Phosphoinositide-3 Kinase Inhibitors
030304 developmental biology
0303 health sciences
Chemistry
Organic Chemistry
Imidazoles
Cell Differentiation
Dabrafenib
differentiation
Cell biology
ERK
medicine.anatomical_structure
Chemistry (miscellaneous)
Molecular Medicine
Schwann Cells
Schwann cell differentiation
Signal transduction
030217 neurology & neurosurgery
medicine.drug
Zdroj: Molecules, Vol 26, Iss 2141, p 2141 (2021)
Molecules
Volume 26
Issue 8
ISSN: 1420-3049
Popis: 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.
Databáze: OpenAIRE
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