SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

Bae, Sung Jun; Ni, Lisheng; Osinski, Adam; Tomchick, Diana R.; Brautigam, Chad A.; Luo, Xuelian

doi:10.7554/eLife.30278

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

Journal Article · Tue Oct 24 00:00:00 EDT 2017 · eLife

DOI:https://doi.org/10.7554/eLife.30278· OSTI ID:1409100

Bae, Sung Jun ^[1]; Ni, Lisheng ^[1]; Osinski, Adam ^[1];

^[2]; Brautigam, Chad A. ^[3];

^[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
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: OTHERNIGMS

OSTI ID:: 1409100

Journal Information:: eLife, Vol. 6, Issue 10, 2017; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.

Country of Publication:: United States

Language:: ENGLISH

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