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

TLDR

YAP is a key regulator of organ size and a candidate oncogene that is inhibited by Hippo pathway‑mediated phosphorylation at Ser127, which promotes 14‑3‑3 binding and cytoplasmic retention. The study aimed to identify CK1δ/ɛ as novel regulators of YAP and to elucidate how Hippo pathway signaling coordinates spatial and temporal control of YAP through S127 phosphorylation and phosphodegron‑mediated degradation. We found that Lats phosphorylates YAP at five HXRXXS motifs, and phosphorylation of Ser381 primes CK1δ/ɛ to create a phosphodegron that recruits SCF β‑TRCP, leading to YAP ubiquitination and degradation, thereby coordinating with Ser127‑mediated cytoplasmic retention to suppress YAP oncogenic activity.

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).