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Title: SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

Abstract

The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.

Authors:
 [1];  [1];  [1]; ORCiD logo [2];  [3]; ORCiD logo [4]
  1. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
  2. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
  3. Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States
  4. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHERNIGMS
OSTI Identifier:
1409100
Resource Type:
Journal Article
Resource Relation:
Journal Name: eLife; Journal Volume: 6; Journal Issue: 10, 2017
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Bae, Sung Jun, Ni, Lisheng, Osinski, Adam, Tomchick, Diana R., Brautigam, Chad A., and Luo, Xuelian. SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK. United States: N. p., 2017. Web. doi:10.7554/eLife.30278.
Bae, Sung Jun, Ni, Lisheng, Osinski, Adam, Tomchick, Diana R., Brautigam, Chad A., & Luo, Xuelian. SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK. United States. doi:10.7554/eLife.30278.
Bae, Sung Jun, Ni, Lisheng, Osinski, Adam, Tomchick, Diana R., Brautigam, Chad A., and Luo, Xuelian. Tue . "SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK". United States. doi:10.7554/eLife.30278.
@article{osti_1409100,
title = {SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK},
author = {Bae, Sung Jun and Ni, Lisheng and Osinski, Adam and Tomchick, Diana R. and Brautigam, Chad A. and Luo, Xuelian},
abstractNote = {The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.},
doi = {10.7554/eLife.30278},
journal = {eLife},
number = 10, 2017,
volume = 6,
place = {United States},
year = {Tue Oct 24 00:00:00 EDT 2017},
month = {Tue Oct 24 00:00:00 EDT 2017}
}