Mitogen-activated protein kinase activated protein kinase 2 (MK2) participates in p38 MAPK regulated control of oligodendrocyte differentiation.
The p38 mitogen-activated protein kinases (p38 MAPKs) are a family of kinases that regulate a number of cellular functions including cell migration, proliferation, and differentiation. We have previously reported a role for p38 MAPK in the regulation of oligodendrocyte (OLG) differentiation and Schwann cell myelination. Here, we extend our previous findings by showing that a p38 substrate, mitogen-activated protein kinase activated protein kinase 2 (MK2) is a downstream element of the p38 signaling pathway responsible for effecting OLG differentiation. Inhibition of MK2 activity in oligodendrocyte progenitors (OLPs) using CMPD1 [4-(2'-fluorobiphenyl-4-yl)-N-(4-hydroxyphenyl)-butyramide] blocked the activation of MK2 and resulted in decreased accumulation of myelin-differentiation markers, including myelin-associated glycoprotein (MAG) and myelin basic protein (MBP). We corroborated these findings using a small-interfering RNA to MK2, which decreased the myelin-specific lipid galactosylceramide and MAG. Treatment of cultures with CMPD1 decreased the steady state levels of mRNA encoding myelin transcription factor 1 (Myt1), MAG, MBP, and Opalin, a transmembrane sialylglycoprotein expressed in oligodendrocytes. In contrast, increases were observed in the mRNA levels of OLG transcriptional repressors, including transcription factor 4 (Tcf4), Notch1, and inhibitor of differentiation 2 (Id2). Furthermore, we found that the predominantly expressed isoform of p38 in OLGs, p38alpha, and MK2 can form coimmunoprecipitable complexes in OLPs and OLGs. Our results demonstrate that the p38-MK2 pathway is a component of the signaling cascade regulating OLG differentiation.
Haines
Jeffery D
JD
Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada.
Fang
Jun
J
Mushynski
Walter E
WE
Almazan
Guillermina
G
D000818:Animals; D000831:Animals, Newborn; D001713:Biphenyl Compounds / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000201:enzymology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000166:cytology / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000099190:MAP-Kinase-Activated Kinase 2
D001713:Biphenyl Compounds; D047908:Intracellular Signaling Peptides and Proteins; D009185:Myelin Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C492719:p38alpha inhibitor CMPD1