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  Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival

Kudryashova V, T., Dabral, S., Nayakanti, S., Ray, A., Goncharov, D. A., Avolio, T., et al. (2022). Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival. CIRCULATION RESEARCH, 130(5), 760-778. doi:10.1161/CIRCRESAHA.121.319100.

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Kudryashova V, Tatiana, Author
Dabral, Swati1, Author              
Nayakanti, Sreenath, Author
Ray, Arnab, Author
Goncharov, Dmitry A., Author
Avolio, Theodore, Author
Shen, Yuanjun, Author
Rode, Analise, Author
Pena, Andressa, Author
Jiang, Lifeng, Author
Lin, Derek, Author
Baust, Jeffrey, Author
Bachman, Timothy N., Author
Graumann, Johannes2, Author              
Ruppert, Clemens, Author
Guenther, Andreas, Author
Schmoranzer, Mario1, Author              
Grobs, Yann, Author
Lemay, Sarah Eve, Author
Tremblay, Eve, Author
Breuils-Bonnet, Sandra, AuthorBoucherat, Olivier, AuthorMora, Ana L., AuthorDeLisser, Horace, AuthorZhao, Jing, AuthorZhao, Yutong, AuthorBonnet, Sebastien, AuthorSeeger, Werner1, Author              Pullamsetti, Soni S.1, Author              Goncharova, Elena A., Author more..
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              
2Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591705              

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 Abstract: Rationale: The MSTs (mammalian Ste20-like kinases) 1/2 are members of the HIPPO pathway that act as growth suppressors in adult proliferative diseases. Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small PAs, pulmonary vascular remodeling, and the rise of pulmonary arterial pressure. The role of MST1/2 in PAH is currently unknown. Objective: To investigate the roles and mechanisms of the action of MST1 and MST2 in PAH. Methods and Results: Using early-passage pulmonary vascular cells from PAH and nondiseased lungs and mice with smooth muscle-specific tamoxifen-inducible Mst1/2 knockdown, we found that, in contrast to canonical antiproliferative/proapoptotic roles, MST1/2 act as proproliferative/prosurvival molecules in human PAH pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts and support established pulmonary vascular remodeling and pulmonary hypertension in mice with SU5416/hypoxia-induced pulmonary hypertension. By using unbiased proteomic analysis, gain- and loss-of function approaches, and pharmacological inhibition of MST1/2 kinase activity by XMU-MP-1, we next evaluated mechanisms of regulation and function of MST1/2 in PAH pulmonary vascular cells. We found that, in PAH pulmonary arterial adventitial fibroblasts, the proproliferative function of MST1/2 is caused by IL-6-dependent MST1/2 overexpression, which induces PSMC6-dependent downregulation of forkhead homeobox type O 3 and hyperproliferation. In PAH pulmonary arterial vascular smooth muscle cells, MST1/2 acted via forming a disease-specific interaction with BUB3 and supported ECM (extracellular matrix)- and USP10-dependent BUB3 accumulation, upregulation of Akt-mTORC1, cell proliferation, and survival. Supporting our in vitro observations, smooth muscle-specific Mst1/2 knockdown halted upregulation of Akt-mTORC1 in small muscular PAs of mice with SU5416/hypoxia-induced pulmonary hypertension. Conclusions: Together, this study describes a novel proproliferative/prosurvival role of MST1/2 in PAH pulmonary vasculature, provides a novel mechanistic link from MST1/2 via BUB3 and forkhead homeobox type O to the abnormal proliferation and survival of pulmonary arterial vascular smooth muscle cells and pulmonary arterial adventitial fibroblasts, remodeling and pulmonary hypertension, and suggests new target pathways for therapeutic intervention.

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 Dates: 2022-02-072022-03-04
 Publication Status: Published in print
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Title: CIRCULATION RESEARCH
Source Genre: Journal
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Pages: - Volume / Issue: 130 (5) Sequence Number: - Start / End Page: 760 - 778 Identifier: ISSN: 0009-7330