Cdk5 regulates differentiation of oligodendrocyte precursor cells through the direct phosphorylation of paxillin.
Oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes (OLs) in order to form myelin, which is required for the rapid propagation of action potentials in the vertebrate nervous system. In spite of the considerable clinical importance of myelination, little is known about the basic molecular mechanisms underlying OL differentiation and myelination. Here, we show that cyclin-dependent kinase (Cdk) 5 is activated following the induction of differentiation, and that the Cdk5 inhibitor roscovitine inhibits OL differentiation. The complexity of the OL processes is also diminished after knocking down endogenous Cdk5 using RNAi. We also show that the focal adhesion protein paxillin is directly phosphorylated at Ser244 by Cdk5. Transfection of a paxillin construct harboring a Ser244 to Ala mutation dramatically inhibits its morphological effects. Importantly, phosphorylation of paxillin at Ser244 reduces its interaction with focal adhesion kinase (FAK). Taken together, these results suggest that phosphorylation of paxillin by Cdk5 is a key mechanism in OL differentiation and may ultimately regulate myelination.
Department of Pharmacology, National Research Institute for Child Health and Development, Okura, Setagaya, Tokyo 157-8535, Japan.
Yuki
Y
Miyamoto
Junji
J
Yamauchi
Jonah R
JR
Chan
Atsumasa
A
Okada
Yasuhiro
Y
Tomooka
Shin-ichi
S
Hisanaga
Akito
A
Tanoue
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D009186:Myelin Sheath / Q000502:physiology*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine
D051419:Paxillin; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D051417:Focal Adhesion Kinase 1; D051360:Cyclin-Dependent Kinase 5