CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus

Yong Suk Cho, Shuang Li, Xiaohui Wang, Jian Zhu, Shu Zhuo, Yuhong Han, Tao Yue, Yingzi Yang, Jin Jiang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Hippo signaling controls organ size and tumor progression through a conserved pathway leading to nuclear translocation of the transcriptional effector Yki/Yap/Taz. Most of our understanding of Hippo signaling pertains to its cytoplasmic regulation, but how the pathway is controlled in the nucleus remains poorly understood. Here we uncover an evolutionarily conserved mechanism by which CDK7 promotes Yki/Yap/Taz stabilization in the nucleus to sustain Hippo pathway outputs. We found that a modular E3 ubiquitin ligase complex CRL4DCAF12 binds and targets Yki/Yap/Taz for ubiquitination and degradation, whereas CDK7 phosphorylates Yki/Yap/Taz at S169/S128/S90 to inhibit CRL4DCAF12 recruitment, leading to Yki/Yap/Taz stabilization. As a consequence, inactivation of CDK7 reduced organ size and inhibited tumor growth, which could be reversed by restoring Yki/Yap activity. Our study identifies an unanticipated layer of Hippo pathway regulation, defines a novel mechanism by which CDK7 regulates tissue growth, and implies CDK7 as a drug target for Yap/Taz-driven cancer.

Original languageEnglish (US)
Pages (from-to)53-71
Number of pages19
JournalGenes & development
Volume34
Issue number1-2
DOIs
StatePublished - Jan 1 2020

Keywords

  • CDK7
  • CRL4
  • Cul4
  • DCAF12
  • Hippo
  • Taz
  • Yap
  • Yki
  • cancer
  • organ size

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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