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Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival.
Kudryashova, Tatiana V; Dabral, Swati; Nayakanti, Sreenath; Ray, Arnab; Goncharov, Dmitry A; Avolio, Theodore; Shen, Yuanjun; Rode, Analise; Pena, Andressa; Jiang, Lifeng; Lin, Derek; Baust, Jeffrey; Bachman, Timothy N; Graumann, Johannes; Ruppert, Clemens; Guenther, Andreas; Schmoranzer, Mario; Grobs, Yann; Eve Lemay, Sarah; Tremblay, Eve; Breuils-Bonnet, Sandra; Boucherat, Olivier; Mora, Ana L; DeLisser, Horace; Zhao, Jing; Zhao, Yutong; Bonnet, Sébastien; Seeger, Werner; Pullamsetti, Soni S; Goncharova, Elena A.
Affiliation
  • Kudryashova TV; 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.).
  • Dabral S; Pittsburgh 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.).
  • Nayakanti S; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh (T.V.K., A.L.M., E.A.G.).
  • Ray A; 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.).
  • Goncharov DA; 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.).
  • Avolio T; Pittsburgh 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.).
  • Shen Y; 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.).
  • Rode A; Pittsburgh 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.).
  • Pena A; Pittsburgh 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.).
  • Jiang L; 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.).
  • Lin D; Pittsburgh 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.).
  • Baust J; Pittsburgh 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.).
  • Bachman TN; Pittsburgh 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.).
  • Graumann J; 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.).
  • Ruppert C; 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.).
  • Guenther A; Pittsburgh 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.).
  • Schmoranzer M; Pittsburgh 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.).
  • Grobs Y; Biomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (J.G.).
  • Eve Lemay S; Department of Internal Medicine, Justus Liebig University, Giessen, Germany (C.R., A.G.).
  • Tremblay E; Department of Internal Medicine, Justus Liebig University, Giessen, Germany (C.R., A.G.).
  • Breuils-Bonnet S; 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.).
  • Boucherat O; Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).
  • Mora AL; Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).
  • DeLisser H; Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).
  • Zhao J; Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).
  • Zhao Y; Department of Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada (Y.G., S.E.L., E.T., S.B.-B., O.B., S.B.).
  • Bonnet S; Pittsburgh 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.).
  • Seeger W; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh (T.V.K., A.L.M., E.A.G.).
  • Pullamsetti SS; Department of Pathology and Laboratory Medicine, Pulmonary Vascular Disease Program, University of Pennsylvania Perelman School of Medicine, Philadelphia (H.D.).
  • Goncharova EA; The Ohio State University College of Medicine, Columbus (J.Z., Y.Z.).
Circ Res ; 130(5): 760-778, 2022 03 04.
Article in En | MEDLINE | ID: mdl-35124974
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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Full text: 1 Database: MEDLINE Main subject: Chromosomal Proteins, Non-Histone / Cell Cycle Proteins / Forkhead Transcription Factors / Poly-ADP-Ribose Binding Proteins / Pulmonary Arterial Hypertension / Hypertension, Pulmonary Limits: Animals Language: En Year: 2022 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Chromosomal Proteins, Non-Histone / Cell Cycle Proteins / Forkhead Transcription Factors / Poly-ADP-Ribose Binding Proteins / Pulmonary Arterial Hypertension / Hypertension, Pulmonary Limits: Animals Language: En Year: 2022 Type: Article