Sphingosine-1-phosphate induces airway smooth muscle cell proliferation, migration, and contraction by modulating Hippo signaling effector YAP

Lu Liu; Cui Zhai; Yilin Pan; Yanting Zhu; Wenhua Shi; Jian Wang; Xin Yan; Xiaofan Su; Yang Song; Li Gao; Manxiang Li

doi:10.1152/ajplung.00554.2017

Sphingosine-1-phosphate induces airway smooth muscle cell proliferation, migration, and contraction by modulating Hippo signaling effector YAP

Am J Physiol Lung Cell Mol Physiol. 2018 Oct 1;315(4):L609-L621. doi: 10.1152/ajplung.00554.2017. Epub 2018 Jul 12.

Authors

Lu Liu¹, Cui Zhai¹, Yilin Pan¹, Yanting Zhu¹, Wenhua Shi¹, Jian Wang¹, Xin Yan¹, Xiaofan Su¹, Yang Song¹, Li Gao², Manxiang Li¹

Affiliations

¹ Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi , People's Republic of China.
² Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland.

PMID: 29999407
DOI: 10.1152/ajplung.00554.2017

Abstract

Sphingosine-1-phosphate (S1P), a bioactive lipid, has been shown to be elevated in the airways of individuals with asthma and modulates the airway smooth muscle cell (ASMC) functions, yet its underlying molecular mechanisms are not completely understood. The aim of the present study is to address this issue. S1P induced yes-associated protein (YAP) dephosphorylation and nuclear localization via the S1PR_2/3/Rho-associated protein kinase (ROCK) pathway, and this in turn increased forkhead box M1 (FOXM1) and cyclin D1 expression leading to ASMC proliferation, migration, and contraction. Pretreatment of cells with S1PR₂ antagonist JTE013, S1PR₃ antagonist CAY10444, or ROCK inhibitor Y27632 blocked S1P-induced alterations of YAP, FOXM1, cyclin D1, and ASMC proliferation, migration, and contraction. In addition, prior silencing of YAP or FOXM1 with siRNA reversed the effect of S1P on ASMC functions. Taken together, our study indicates that S1P stimulates ASMC proliferation, migration, and contraction by binding to S1PR_2/3 and modulating ROCK/YAP/FOXM1 axis and suggests that targeting this pathway might have potential value in the management of asthma.

Keywords: ASMCs; FOXM1; S1P; YAP.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Cell Movement / drug effects*
Cell Proliferation / drug effects*
Cells, Cultured
Forkhead Box Protein M1 / genetics
Forkhead Box Protein M1 / metabolism
Gene Expression Regulation / drug effects*
Lysophospholipids / pharmacology*
Myocytes, Smooth Muscle / drug effects
Myocytes, Smooth Muscle / metabolism
Myocytes, Smooth Muscle / pathology*
Rats
Rats, Sprague-Dawley
Receptors, Lysosphingolipid / genetics
Receptors, Lysosphingolipid / metabolism
Signal Transduction / drug effects*
Sphingosine / analogs & derivatives*
Sphingosine / pharmacology
Sphingosine-1-Phosphate Receptors
YAP-Signaling Proteins
rho-Associated Kinases / genetics
rho-Associated Kinases / metabolism

Substances

Apoptosis Regulatory Proteins
Forkhead Box Protein M1
Foxm1 protein, rat
Lysophospholipids
Receptors, Lysosphingolipid
S1PR3 protein, rat
Sphingosine-1-Phosphate Receptors
YAP-Signaling Proteins
Yap1 protein, rat
sphingosine-1-phosphate receptor-2, rat
sphingosine 1-phosphate
ROCK1 protein, rat
ROCK2 protein, rat
rho-Associated Kinases
Sphingosine