GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity.
Neurons are highly polarized and comprised of two structurally and functionally distinct parts, an axon and dendrites. We previously showed that collapsin response mediator protein-2 (CRMP-2) is critical for specifying axon/dendrite fate, possibly by promoting neurite elongation via microtubule assembly. Here, we showed that glycogen synthase kinase-3beta (GSK-3beta) phosphorylated CRMP-2 at Thr-514 and inactivated it. The expression of the nonphosphorylated form of CRMP-2 or inhibition of GSK-3beta induced the formation of multiple axon-like neurites in hippocampal neurons. The expression of constitutively active GSK-3beta impaired neuronal polarization, whereas the nonphosphorylated form of CRMP-2 counteracted the inhibitory effects of GSK-3beta, indicating that GSK-3beta regulates neuronal polarity through the phosphorylation of CRMP-2. Treatment of hippocampal neurons with neurotrophin-3 (NT-3) induced inactivation of GSK-3beta and dephosphorylation of CRMP-2. Knockdown of CRMP-2 inhibited NT-3-induced axon outgrowth. These results suggest that NT-3 decreases phosphorylated CRMP-2 and increases nonphosphorylated active CRMP-2, thereby promoting axon outgrowth.
Yoshimura
Takeshi
T
Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan.
Kawano
Yoji
Y
Arimura
Nariko
N
Kawabata
Saeko
S
Kikuchi
Akira
A
Kaibuchi
Kozo
K
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D019556:COS Cells; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology*; D003712:Dendrites / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D020933:Neurotrophin 3 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats
D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; C095114:collapsin response mediator protein-2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3