Saishu Yoshida: Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan. ORCID
Akira Kawamura: Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan. ORCID
Katsuhiko Aoki: Radioisotope Research Facilities, The Jikei University School of Medicine, Tokyo 105-8461, Japan. ORCID
Pattama Wiriyasermkul: Center for Stable Isotope Medical Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan. ORCID
Shinya Sugimoto: Department of Bacteriology, The Jikei University School of Medicine, Tokyo 105-8461, Japan. ORCID
Junnosuke Tomiyoshi: Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan. ORCID
Ayasa Tajima: Center for Stable Isotope Medical Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan. ORCID
Yamato Ishida: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Yohei Katoh: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. ORCID
Takehiro Tsukada: Department of Biomolecular Science, Toho University, Chiba 274-8510, Japan. ORCID
Yousuke Tsuneoka: Department of Anatomy, Faculty of Medicine, Toho University, Tokyo 143-8540, Japan. ORCID
Kohji Yamada: Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan. ORCID
Shushi Nagamori: Center for Stable Isotope Medical Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan.
Kazuhisa Nakayama: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. ORCID
Kiyotsugu Yoshida: Department of Biochemistry, The Jikei University School of Medicine, Tokyo 105-8461, Japan. ORCID
Hedgehog (Hh) signaling, an evolutionarily conserved pathway, plays an essential role in development and tumorigenesis, making it a promising drug target. Multiple negative regulators are known to govern Hh signaling; however, how activated Smoothened (SMO) participates in the activation of downstream GLI2 and GLI3 remains unclear. Herein, we identified the ciliary kinase DYRK2 as a positive regulator of the GLI2 and GLI3 transcription factors for Hh signaling. Transcriptome and interactome analyses demonstrated that DYRK2 phosphorylates GLI2 and GLI3 on evolutionarily conserved serine residues at the ciliary base, in response to activation of the Hh pathway. This phosphorylation induces the dissociation of GLI2/GLI3 from suppressor, SUFU, and their translocation into the nucleus. Loss of in mice causes skeletal malformation, but neural tube development remains normal. Notably, DYRK2-mediated phosphorylation orchestrates limb development by controlling cell proliferation. Taken together, the ciliary kinase DYRK2 governs the activation of Hh signaling through the regulation of two processes: phosphorylation of GLI2 and GLI3 downstream of SMO and cilia formation. Thus, our findings of a unique regulatory mechanism of Hh signaling expand understanding of the control of Hh-associated diseases.
