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

Author:

Liu Lu1ORCID,Zhai Cui1,Pan Yilin1,Zhu Yanting1,Shi Wenhua1,Wang Jian1,Yan Xin1,Su Xiaofan1,Song Yang1,Gao Li2,Li Manxiang1

Affiliation:

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

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 S1PR2/3/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 S1PR2/3 and modulating ROCK/YAP/FOXM1 axis and suggests that targeting this pathway might have potential value in the management of asthma.

Funder

National Natural Science Foundation of China (NSFC)

Science and Technology Inernational Copperation and Exchange Program of Shaanxi Province

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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