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1.
Proc Natl Acad Sci U S A ; 121(28): e2320070121, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38968120

RESUMEN

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 Dyrk2 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.


Asunto(s)
Quinasas DyrK , Proteínas Hedgehog , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Transducción de Señal , Proteína Gli2 con Dedos de Zinc , Proteína Gli3 con Dedos de Zinc , Animales , Proteína Gli3 con Dedos de Zinc/metabolismo , Proteína Gli3 con Dedos de Zinc/genética , Proteína Gli2 con Dedos de Zinc/metabolismo , Proteína Gli2 con Dedos de Zinc/genética , Fosforilación , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Ratones , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas/genética , Humanos , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Proliferación Celular , Cilios/metabolismo , Receptor Smoothened/metabolismo , Receptor Smoothened/genética , Proteínas Nucleares , Proteínas Represoras
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