A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCFβ-TRCP

Bin Zhao; Li Li; Karen Tumaneng; Cun-Yu Wang; Kun-Liang Guan

doi:10.1101/gad.1843810

A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF^β-TRCP

¹Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92093-0815, USA;
²Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA;
³Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, University of California at Los Angeles School of Dentistry, Los Angeles, California 90095, USA

Abstract

The Yes-associated protein (YAP) transcription coactivator is a key regulator of organ size and a candidate human oncogene. YAP is inhibited by the Hippo pathway kinase cascade, at least in part via phosphorylation of Ser 127, which results in YAP 14–3–3 binding and cytoplasmic retention. Here we report that YAP is phosphorylated by Lats on all of the five consensus HXRXXS motifs. Phosphorylation of Ser 381 in one of them primes YAP for subsequent phosphorylation by CK1δ/ɛ in a phosphodegron. The phosphorylated phosphodegron then recruits the SCF^β-TRCP E3 ubiquitin ligase, which catalyzes YAP ubiquitination, ultimately leading to YAP degradation. The phosphodegron-mediated degradation and the Ser 127 phosphorylation-dependent translocation coordinately suppress YAP oncogenic activity. Our study identified CK1δ/ɛ as new regulators of YAP and uncovered an intricate mechanism of YAP regulation by the Hippo pathway via both S127 phosphorylation-mediated spatial regulation (nuclear–cytoplasmic shuttling) and the phosphodegron-mediated temporal regulation (degradation).

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