The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway

Authors

  • Isao Oishi,

    1. Department of Genome Sciences, Faculty of Medical Sciences, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japancv
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  • Hiroaki Suzuki,

    1. Department of Genome Sciences, Faculty of Medical Sciences, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japancv
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  • Nobuyuki Onishi,

    1. Department of Genome Sciences, Faculty of Medical Sciences, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japancv
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  • Ritsuko Takada,

    1. Kondoh Differentiation Signalling Project, Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Corporation (JST), Kinki Invention Centre, Sakyo-ku, Kyoto 606-8305, Japan
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  • Shuichi Kani,

    1. Department of Genome Sciences, Faculty of Medical Sciences, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japancv
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  • Bisei Ohkawara,

    1. Department of Molecular Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan
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  • Ikue Koshida,

    1. Kondoh Differentiation Signalling Project, Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Corporation (JST), Kinki Invention Centre, Sakyo-ku, Kyoto 606-8305, Japan
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  • Kentaro Suzuki,

    1. Centre for Animal Resources and Development (CARD) and Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Kumamoto 860-0811, Japan
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  • General Yamada,

    1. Centre for Animal Resources and Development (CARD) and Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Kumamoto 860-0811, Japan
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  • Georg C. Schwabe,

    1. Max-Planck-Institute for Molecular Genetics and Institute for Molecular Genetics, 14195 Berlin-Dahlem, Germany
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  • Stefan Mundlos,

    1. Max-Planck-Institute for Molecular Genetics and Institute for Molecular Genetics, 14195 Berlin-Dahlem, Germany
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  • Hiroshi Shibuya,

    1. Department of Molecular Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan
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  • Shinji Takada,

    Corresponding author
    1. Kondoh Differentiation Signalling Project, Exploratory Research for Advanced Technology (ERATO), Japan Science and Technology Corporation (JST), Kinki Invention Centre, Sakyo-ku, Kyoto 606-8305, Japan
    2. Centre for Molecular and Developmental Biology, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan
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    • a

      Present address: Centre for Integrative Bioscience, Okazaki National Research Institutes, Okazaki, Aichi 444-8585, Japan.

  • Yasuhiro Minami

    Corresponding author
    1. Department of Genome Sciences, Faculty of Medical Sciences, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japancv
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  • Communicated by: Eisuke Nishida

*E-mail: stakada@nibb.ac.jp; minami@ kobe-u.ac.jp

Abstract

Background: Ror2 is an orphan receptor, belonging to the Ror family of receptor tyrosine kinases. Although Ror2 has been shown to play crucial roles in developmental morphogenesis, the precise signalling events that Ror2 mediates remain elusive. Since Ror2 possesses an extracellular cysteine-rich domain (CRD) that resembles the Wnt-binding sites of the Frizzled (Fz) proteins, it is conceivable that Ror2 interacts with members of the Wnt family.

Results: Both Ror2−/− and Wnt5a−/− mice exhibit dwarfism, facial abnormalities, short limbs and tails, dysplasia of lungs and genitals, and ventricular septal defects. In vitro binding assay revealed that Wnt5a binds to the CRD of Ror2. Furthermore, Ror2 associates via its CRD with rFz2, a putative receptor for Wnt5a. Interestingly, Wnt5a and Ror2 activate the non-canonical Wnt pathway, as assessed by activation of JNK in cultured cells and inhibition of convergent extension movements in Xenopus.

Conclusions: Our findings indicate that Wnt5a and Ror2 interact physically and functionally. Ror2 may thus act as a receptor for Wnt5a to activate non-canonical Wnt signalling.

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