Evidence map›Paper›PMID 35124974›Full record

ArticleCirculation research2022

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

Tatiana V Kudryashova, Swati Dabral, Sreenath Nayakanti, Arnab Ray, Dmitry A Goncharov, Theodore Avolio, Yuanjun Shen, Analise Rode, Andressa Pena, Lifeng Jiang and 20 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed
5.1field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

32 citing papers in PubMed, 48 citations in OpenAlex.

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  13. Signaling pathways and targeted therapy for pulmonary hypertension.Signal transduction and targeted therapy · 2025
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  18. The Hippo Pathway in Breast Cancer: The Extracellular Matrix and Hypoxia.International journal of molecular sciences · 2024
    Review
  19. RNAi-MediatedInsects · 2024
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

30 authors at 9 institutions in 4 countries.

Tatiana V Kudryashova *Lung Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis School of Medicine (T.V.K., D.A.G., Y.S., L.J., D.L., E.A.G.).ORCID 0000-0002-2843-5554
Swati Dabral *Department of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.D., S.N., M.S., W.S., S.S.P.).
Sreenath NayakantiDepartment of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.D., S.N., M.S., W.S., S.S.P.).
Arnab RayPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.V.K., A.R., D.A.G., T.A., Y.S., A.R., A.P., J.B., T.N.B., A.L.M., E.A.G.).ORCID 0000-0001-7701-2841
Dmitry A GoncharovLung Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis School of Medicine (T.V.K., D.A.G., Y.S., L.J., D.L., E.A.G.).
Theodore AvolioPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.V.K., A.R., D.A.G., T.A., Y.S., A.R., A.P., J.B., T.N.B., A.L.M., E.A.G.).
Yuanjun ShenLung Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis School of Medicine (T.V.K., D.A.G., Y.S., L.J., D.L., E.A.G.).ORCID 0000-0002-8183-9531
Analise RodePittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.V.K., A.R., D.A.G., T.A., Y.S., A.R., A.P., J.B., T.N.B., A.L.M., E.A.G.).
Andressa PenaPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.V.K., A.R., D.A.G., T.A., Y.S., A.R., A.P., J.B., T.N.B., A.L.M., E.A.G.).
Lifeng JiangLung Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis School of Medicine (T.V.K., D.A.G., Y.S., L.J., D.L., E.A.G.).ORCID 0000-0002-0983-4787
Derek LinLung Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis School of Medicine (T.V.K., D.A.G., Y.S., L.J., D.L., E.A.G.).ORCID 0000-0002-8134-6980
Jeffrey BaustPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.V.K., A.R., D.A.G., T.A., Y.S., A.R., A.P., J.B., T.N.B., A.L.M., E.A.G.).
Timothy N BachmanPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.V.K., A.R., D.A.G., T.A., Y.S., A.R., A.P., J.B., T.N.B., A.L.M., E.A.G.).
Johannes GraumannBiomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (J.G.).ORCID 0000-0002-3015-5850
Clemens RuppertDepartment of Internal Medicine, Justus Liebig University, Giessen, Germany (C.R., A.G.).ORCID 0000-0002-0938-2469
Andreas GuentherDepartment of Internal Medicine, Justus Liebig University, Giessen, Germany (C.R., A.G.).
Mario SchmoranzerDepartment of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.D., S.N., M.S., W.S., S.S.P.).
Yann GrobsDepartment of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).
Sarah Eve LemayDepartment of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).
Eve TremblayDepartment of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).
Sandra Breuils-BonnetDepartment of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).
Olivier BoucheratDepartment of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).ORCID 0000-0002-5251-7488
Ana L MoraPittsburgh Heart, Lung and Blood Vascular Medicine Institute (T.V.K., A.R., D.A.G., T.A., Y.S., A.R., A.P., J.B., T.N.B., A.L.M., E.A.G.).
Horace DeLisserDepartment of Pathology and Laboratory Medicine, Pulmonary Vascular Disease Program, University of Pennsylvania Perelman School of Medicine, Philadelphia (H.D.).
Jing ZhaoThe Ohio State University College of Medicine, Columbus (J.Z., Y.Z.).
Yutong ZhaoThe Ohio State University College of Medicine, Columbus (J.Z., Y.Z.).
Sébastien BonnetDepartment of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).ORCID 0000-0001-5753-1900
Werner SeegerDepartment of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.D., S.N., M.S., W.S., S.S.P.).ORCID 0000-0003-1946-0894
Soni S Pullamsetti *Department of Lung Development and Remodeling, Member of the German Center for Lung Research (DZL), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.D., S.N., M.S., W.S., S.S.P.).
Elena A Goncharova *Lung Center, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis School of Medicine (T.V.K., D.A.G., Y.S., L.J., D.L., E.A.G.).ORCID 0000-0001-7118-6752
Anna Needs Neuroblastoma Answers · USMax Planck Institute for Heart and Lung Research · DEUniversité Laval · CAUniversity of California System · USJustus-Liebig-Universität Gießen · DEThe Ohio State University · USPulmonary and Allergy Associates · USUniversity of Pennsylvania · USUniversity of Pittsburgh · US

Funding

Vascular Subphenotypes of Lung DiseaseP01HL103455 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GLADWIN, MARK T · 2011 to 2020
$26.1M
Pulmonary Hypertension Breakthrough InitiativeR24HL123767 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI ALDRED, MICHEALA A, ERZURUM, SERPIL C. · 2014 to 2017
$10.1M
HIPPO Signaling in Pulmonary Arterial HypertensionR01HL130261 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GONCHAROVA, ELENA · 2016 to 2023
$3.5M
TSC2 Signaling in Pulmonary Arterial HypertensionR01HL113178 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI GONCHAROVA, ELENA · 2012 to 2021
$3.1M
GATA-6 in pulmonary arterial hypertensionR01HL150638 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · PI GONCHAROVA, ELENA, TROJANOWSKA, MARIA · 2020 to 2023
$2.6M
Deubiquitinating and inhibiting Hsp90 by USP40 mitigates lung injuryR01HL151513 · NHLBI · OHIO STATE UNIVERSITY · PI ZHAO, JING · 2020 to 2023
$1.7M
Regulation of Histone Acetyltransferase Stability In SepsisR01GM115389 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI ZHAO, JING · 2015 to 2019
$1.5M
NHLBI NIH HHS P01 HL103455NHLBI NIH HHS R01 HL113178NHLBI NIH HHS R01 HL130261NHLBI NIH HHS R01 HL150638NHLBI NIH HHS R01 HL151513NHLBI NIH HHS R24 HL123767NIGMS NIH HHS R01 GM115389
6 · The paper itself

Abstract

rationaleThe 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.

objectiveTo investigate the roles and mechanisms of the action of MST1 and MST2 in PAH. METHODS AND

resultsUsing 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.

conclusionsTogether, 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.

Indexed as

Hypertension, PulmonaryPulmonary Arterial HypertensionAnimalsCell Cycle ProteinsCell ProliferationCells, CulturedChromosomal Proteins, Non-HistoneForkhead Transcription FactorsHypoxiaMammalsMechanistic Target of Rapamycin Complex 1MiceMyocytes, Smooth MusclePoly-ADP-Ribose Binding ProteinsProteomicsProto-Oncogene Proteins c-aktBub3 protein, mouseCell Cycle ProteinsChromosomal Proteins, Non-HistoneForkhead Transcription FactorsMechanistic Target of Rapamycin Complex 1Poly-ADP-Ribose Binding ProteinsProto-Oncogene Proteins c-aktanimalshypoxiamiceproteomicpulmonary artery

Identifiers

PMID35124974
PMCPMC8897250
OpenAlexW4210712723

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.