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Molecular and Cellular Biology, November 2005, p. 9973-9984, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.9973-9984.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phosphorylation by Rho Kinase Regulates CRMP-2 Activity in Growth Cones

Nariko Arimura,1,2 Céline Ménager,1 Yoji Kawano,1,5 Takeshi Yoshimura,1 Saeko Kawabata,1 Atsushi Hattori,1 Yuko Fukata,1 Mutsuki Amano,1 Yoshio Goshima,3 Masaki Inagaki,2 Nobuhiro Morone,4 Jiro Usukura,4 and Kozo Kaibuchi1*

Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya, Aichi 466-8550, Japan,1 Division of Biochemistry, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa, Nagoya, Aichi 464-8681, Japan,2 Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan,3 Department of Anatomy, School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya, Aichi 466-8550, Japan,4 Division of Molecular and Cell Biology, Institute for Medical Science, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibumachi, Tochigi 321-0293, Japan5

Received 18 May 2005/ Returned for modification 27 June 2005/ Accepted 29 August 2005

Collapsin response mediator protein 2 (CRMP-2) enhances the advance of growth cones by regulating microtubule assembly and Numb-mediated endocytosis. We previously showed that Rho kinase phosphorylates CRMP-2 during growth cone collapse; however, the roles of phosphorylated CRMP-2 in growth cone collapse remain to be clarified. Here, we report that CRMP-2 phosphorylation by Rho kinase cancels the binding activity to the tubulin dimer, microtubules, or Numb. CRMP-2 binds to actin, but its binding is not affected by phosphorylation. Electron microscopy revealed that CRMP-2 localizes on microtubules, clathrin-coated pits, and actin filaments in dorsal root ganglion neuron growth cones, while phosphorylated CRMP-2 localizes only on actin filaments. The phosphomimic mutant of CRMP-2 has a weakened ability to enhance neurite elongation. Furthermore, ephrin-A5 induces phosphorylation of CRMP-2 via Rho kinase during growth cone collapse. Taken together, these results suggest that Rho kinase phosphorylates CRMP-2, and inactivates the ability of CRMP-2 to promote microtubule assembly and Numb-mediated endocytosis, during growth cone collapse.

* Corresponding author. Mailing address: Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya, Aichi 466-8550, Japan. Phone: 81 52 744 2074. Fax: 81 52 744 2083. E-mail: kaibuchi{at}med.nagoya-u.ac.jp.

Molecular and Cellular Biology, November 2005, p. 9973-9984, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.9973-9984.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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