Phosphorylation of Drebrin by Cyclin-dependent Kinase 5 and Its role in neuronal migration

Kazuya Tanabe, Hiroyuki Yamazaki, Yutaka Inaguma, Akiko Asada, Taeko Kimura, Junya Takahashi, Masato Taoka, Toshio Ohshima, Teiichi Furuichi, Toshiaki Isobe, Koh Ichi Nagata, Tomoaki Shirao, Shin Ichi Hisanaga

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    Abstract

    Cyclin-dependent kinase 5 (Cdk5)-p35 is a proline-directed Ser/Thr kinase which plays a key role in neuronal migration, neurite outgrowth, and spine formation during brain development. Dynamic remodeling of cytoskeletons is required for all of these processes. Cdk5-p35 phosphorylates many cytoskeletal proteins, but it is not fully understood how Cdk5-p35 regulates cytoskeletal reorganization associated with neuronal migration. Since actin filaments are critical for the neuronal movement and process formation, we aimed to find Cdk5 substrates among actin-binding proteins. In this study, we isolated actin gels from mouse brain extracts, which contain many actin-binding proteins, and phosphorylated them by Cdk5-p35 in vitro. Drebrin, a side binding protein of actin filaments and well known for spine formation, was identified as a phosphorylated protein. Drebrin has two isoforms, an embryonic form drebrin E and an adult type long isoform drebrin A. Ser142 was identified as a common phosphorylation site to drebrin E and A and Ser342 as a drebrin A-specific site. Phosphorylated drebrin is localized at the distal area of total drebrin in the growth cone of cultured primary neurons. By expressing nonphosphorylatable or phosphorylation mimicking mutants in developing neurons in utero, the reversible phosphorylation/dephosphorylation reaction of drebrin was shown to be involved in radial migration of cortical neurons. These results suggest that Cdk5-p35 regulates neuronal migration through phosphorylation of drebrin in growth cone processes. Copyright:

    Original languageEnglish
    Article numbere92291
    JournalPLoS One
    Volume9
    Issue number3
    DOIs
    Publication statusPublished - 2014 Mar 17

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    ASJC Scopus subject areas

    • Agricultural and Biological Sciences(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Medicine(all)

    Cite this

    Tanabe, K., Yamazaki, H., Inaguma, Y., Asada, A., Kimura, T., Takahashi, J., Taoka, M., Ohshima, T., Furuichi, T., Isobe, T., Nagata, K. I., Shirao, T., & Hisanaga, S. I. (2014). Phosphorylation of Drebrin by Cyclin-dependent Kinase 5 and Its role in neuronal migration. PLoS One, 9(3), [e92291]. https://doi.org/10.1371/journal.pone.0092291