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

Yong suk Cho, Jian Zhu, Shuangxi Li, Bing Wang, Yuhong Han and Jin Jiang ()
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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
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

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04090-2

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