The protein phosphatase PPM1A dephosphorylates and activates YAP to govern mammalian intestinal and liver regeneration.

Ruyuan Zhou,Qirou Wu,Jian Zou,Jun Qin,Liming Wu,Mengqiu Wang,Xiao Li,Xia Lin,Seema Irani,Hai Song,Xiaojian Wang,Fansen Meng,Pinglong Xu,Yan Jessie Zhang,Qian Zhang,Fei Zhang,Tingbo Liang,Shengduo Liu,Xin‐Hua Feng

doi:10.1371/journal.pbio.3001122

Abstract

The Hippo-YAP pathway responds to diverse environmental cues to manage tissue homeostasis, organ regeneration, tumorigenesis, and immunity. However, how phosphatase(s) directly target Yes-associated protein (YAP) and determine its physiological activity are still inconclusive. Here, we utilized an unbiased phosphatome screening and identified protein phosphatase magnesium-dependent 1A (PPM1A/PP2Cα) as the bona fide and physiological YAP phosphatase. We found that PPM1A was associated with YAP/TAZ in both the cytoplasm and the nucleus to directly eliminate phospho-S127 on YAP, which conferring YAP the nuclear distribution and transcription potency. Accordingly, genetic ablation or depletion of PPM1A in cells, organoids, and mice elicited an enhanced YAP/TAZ cytoplasmic retention and resulted in the diminished cell proliferation, severe gut regeneration defects in colitis, and impeded liver regeneration upon injury. These regeneration defects in murine model were largely rescued via a genetic large tumor suppressor kinase 1 (LATS1) deficiency or the pharmacological inhibition of Hippo-YAP signaling. Therefore, we identify a physiological phosphatase of YAP/TAZ, describe its critical effects in YAP/TAZ cellular distribution, and demonstrate its physiological roles in mammalian organ regeneration.

Highlights

Discovered in Drosophila, the Hippo pathway is highly conserved in evolution [1,2,3,4]
The reporter assays revealed that protein phosphatase magnesium-dependent 1A (PPM1A)/PP2Cα, as well as previously reported PP2A [26,27,28], substantially enhanced the transcriptional potency of Yes-associated protein (YAP)-transcriptional enhanced associate domain (TEAD) that were suppressed by mammalian sterile 20-like kinase 1 (MST1) (Fig 1A and S1A Fig)
In addition to relieving the MST1-driven inhibition of YAP (Fig 1B), PPM1A reversed the YAP suppression triggered by large tumor suppressor kinase 1 (LATS1) (Fig 1C), and MAP4K1 (Fig 1D), another upstream kinase of the LATS kinases [9]

Summary

Introduction

Discovered in Drosophila, the Hippo pathway is highly conserved in evolution [1,2,3,4]. Four tumor suppressors, constituting the Hpo-Sav/MST-SAV complex and the WtsMats/LATS-MOB complex, sequentially govern the cellular localization, activity, and fate of signaling effectors Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). In response to unfavorable growth conditions and mediated by the upstream kinases including MST, MAP4Ks, TAO, and AMPK, LATS kinases phosphorylate YAP and TAZ [5,6,7,8,9,10,11,12,13,14]. Large tumor suppressor kinase 1 and 2 (LATS1/2)-mediated phosphorylation retains YAP/TAZ in the cytoplasm for sequestration, ubiquitination, and degradation [15,16]. Physiological and pathological functions of the Hippo pathway are gradually established, in the development, homeostasis, and regeneration of organs including liver, heart, intestine, brain and central nervous system (CNS), lung, kidney etc. Physiological and pathological functions of the Hippo pathway are gradually established, in the development, homeostasis, and regeneration of organs including liver, heart, intestine, brain and central nervous system (CNS), lung, kidney etc. [18], and in the diseases of cancer, immune disorder, cardiovascular dysfunction [17,19]

Methods

Results

Conclusion