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Regulation of Yki/Yap subcellular localization and Hpo signaling by a nuclear kinase PRP4K

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  • Yong suk Cho

    (University of Texas Southwestern Medical Center at Dallas)

  • Jian Zhu

    (University of Texas Southwestern Medical Center at Dallas
    Xinxiang Medical University)

  • Shuangxi Li

    (University of Texas Southwestern Medical Center at Dallas)

  • Bing Wang

    (University of Texas Southwestern Medical Center at Dallas)

  • Yuhong Han

    (University of Texas Southwestern Medical Center at Dallas)

  • Jin Jiang

    (University of Texas Southwestern Medical Center at Dallas
    University of Texas Southwestern Medical Center at Dallas)

Abstract

Hippo (Hpo) signaling pathway controls tissue growth by regulating the subcellular localization of Yorkie (Yki)/Yap via a cytoplasmic kinase cassette containing an upstream kinase Hpo/MST1/2 and a downstream kinase Warts (Wts)/Lats1/2. Here we show that PRP4K, a kinase involved in mRNA splicing, phosphorylates Yki/Yap in the nucleus to prevent its nuclear accumulation and restrict Hpo pathway target gene expression. PRP4K inactivation accelerates whereas excessive PRP4K inhibits Yki-driven tissue overgrowth. PRP4K phosphorylates a subset of Wts/Lats1/2 sites on Yki/Yap to inhibit the binding of Yki/Yap to the Scalloped (Sd)/TEAD transcription factor and exclude Yki/Yap nuclear localization depending on nuclear export. Furthermore, PRP4K inhibits proliferation and invasiveness of cultured breast cancer cells and its high expression correlates with good prognosis in breast cancer patients. Our study unravels an unanticipated layer of Hpo pathway regulation and suggests that PRP4K-mediated Yki/Yap phosphorylation in the nucleus provides a fail-safe mechanism to restrict aberrant pathway activation.

Suggested Citation

  • Yong suk Cho & Jian Zhu & Shuangxi Li & Bing Wang & Yuhong Han & Jin Jiang, 2018. "Regulation of Yki/Yap subcellular localization and Hpo signaling by a nuclear kinase PRP4K," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04090-2
    DOI: 10.1038/s41467-018-04090-2
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    Cited by:

    1. Yue Li & Pengzhen Dong & Yang Yang & Tianyu Guo & Quanyi Zhao & Dan Miao & Huanle Li & Tianfeng Lu & Fanning Xia & Jialan Lyu & Jun Ma & Thomas B. Kornberg & Qiang Zhang & Hai Huang, 2022. "Metabolic control of progenitor cell propagation during Drosophila tracheal remodeling," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Xu Li & Shu Zhuo & Ting Zhuang & Yong Suk Cho & Guojin Wu & Yuchen Liu & Kun Mu & Kai Zhang & Peng Su & Yingzi Yang & Cheng Cheng Zhang & Jian Zhu & Jin Jiang, 2022. "YAP inhibits ERα and ER+ breast cancer growth by disrupting a TEAD-ERα signaling axis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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