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

Genes Dev. 2020 Jan 1;34(1-2):53-71. doi: 10.1101/gad.333146.119. Epub 2019 Dec 19.

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.

Keywords: CDK7; CRL4; Cul4; DCAF12; Hippo; Taz; Yap; Yki; cancer; organ size.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics*
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / enzymology*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Knockdown Techniques
  • Humans
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / physiopathology
  • Mice
  • Nuclear Proteins / metabolism*
  • Organ Size / genetics
  • Phenylenediamines / pharmacology
  • Proteolysis
  • Pyrimidines / pharmacology
  • Trans-Activators / metabolism*

Substances

  • Antineoplastic Agents
  • Dis3 protein, Drosophila
  • Drosophila Proteins
  • Nuclear Proteins
  • Phenylenediamines
  • Pyrimidines
  • THZ1 compound
  • Trans-Activators
  • Yki protein, Drosophila
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase-activating kinase