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

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

Cho YS#1, Li S#1, Wang X2,3, Zhu J1, Zhuo S1, Han Y1, Yue T4, Yang Y2,3, Jiang J1,5.

Author information

1
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
2
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02215, USA.
3
Harvard Stem Cell Institute, Boston, Massachusetts 02215, USA.
4
Center for the Genetics and Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
5
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
#
Contributed equally

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

PMID:
31857346
PMCID:
PMC6938674
[Available on 2020-07-01]
DOI:
10.1101/gad.333146.119
[Indexed for MEDLINE]

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