PTEN Participates in Airway Remodeling of Asthma by Regulating CD38/Ca/CREB Signaling

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2020 Sep 5

PMID 32889801

Citations 13

Authors

Yuanyuan Wu

Yiyi Lu

Fan Zou

Xinping Fan

Xudong Li

Hongni Zhang

Haijuan Chen

Xiuzhen Sun

Yun Liu

Affiliations

Soon will be listed here.

Abstract

Both phosphatase and tensin homologue deleted on chromosome ten (PTEN) and cluster of differentiation 38 (CD38) have been suggested to be key regulators of the pathogenesis of asthma. However, the precise role and molecular mechanisms by which PTEN and CD38 are involved in airway remodeling throughout asthma pathogenesis remains poorly understood. This study aimed to elucidate the role of PTEN and CD38 in airway remodeling of asthma. Exposure to tumor necrosis factor-α (TNF-α) in airway smooth muscle (ASM) cells markedly decreased PTEN expression, and increased expression of CD38. Overexpression of PTEN suppressed the expression of CD38 and downregulated proliferation and migration induced by TNF-α stimulation, which was partially reversed by CD38 overexpression. PTEN/CD38 axis regulated Ca2+ levels and cyclic AMP response-element binding protein (CREB) phosphorylation in TNF-α-stimulated ASM cells. The in vitro knockdown of CD38 or overexpression of PTEN remarkably restricted airway remodeling and decreased Ca2+ concentrations and CREB phosphorylation in asthmatic mice. CD38 overexpression abolished the inhibitory effects of PTEN overexpression on airway remodeling. These findings demonstrate that PTEN inhibits airway remodeling of asthma through the downregulation of CD38-mediated Ca2+/CREB signaling, highlighting a key role of PTEN/CD38/Ca2+/CREB signaling in the molecular pathogenesis of asthma.

Citing Articles

Peripheral blood miRNAs are associated with airflow below threshold in children with asthma.

Tiwari A, Hobbs B, Sharma R, Li J, Kho A, Amr S Respir Res. 2025; 26(1):38.

PMID: 39856653 PMC: 11763123. DOI: 10.1186/s12931-025-03116-w.

Fibroblast Growth Factor 21 Confers Protection Against Asthma Through Inhibition of NLRP3 Inflammasome Activation.

Liu Y, Li J, Wu Z, Wu S, Yang X Inflammation. 2024; .

PMID: 39730972 DOI: 10.1007/s10753-024-02222-z.

Potential association between obstructive lung diseases and cognitive decline.

Figat M, Wisniewska A, Plichta J, Milkowska-Dymanowska J, Majewski S, Karbownik M Front Immunol. 2024; 15:1363373.

PMID: 39104536 PMC: 11298337. DOI: 10.3389/fimmu.2024.1363373.

Gene-Smoking Interaction Analysis for the Identification of Novel Asthma-Associated Genetic Factors.

Cha J, Choi S Int J Mol Sci. 2023; 24(15).

PMID: 37569643 PMC: 10419280. DOI: 10.3390/ijms241512266.

Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 virus and Staphylococcus aureus infections.

Liao S, Huang Y, Zhang J, Xiong Q, Chi M, Yang L Respir Res. 2023; 24(1):175.

PMID: 37407993 PMC: 10324174. DOI: 10.1186/s12931-023-02477-4.

References

Tirumurugaan K, Jude J, Kang B, Panettieri R, Walseth T, Kannan M . TNF-alpha induced CD38 expression in human airway smooth muscle cells: role of MAP kinases and transcription factors NF-kappaB and AP-1. Am J Physiol Lung Cell Mol Physiol. 2007; 292(6):L1385-95. DOI: 10.1152/ajplung.00472.2006. View

Masoli M, Fabian D, Holt S, Beasley R . The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004; 59(5):469-78. DOI: 10.1111/j.1398-9995.2004.00526.x. View

Salter B, Pray C, Radford K, Martin J, Nair P . Regulation of human airway smooth muscle cell migration and relevance to asthma. Respir Res. 2017; 18(1):156. PMC: 5559796. DOI: 10.1186/s12931-017-0640-8. View

Kwak Y, Song C, Yi H, Hwang P, Kim J, Lee K . Involvement of PTEN in airway hyperresponsiveness and inflammation in bronchial asthma. J Clin Invest. 2003; 111(7):1083-92. PMC: 152583. DOI: 10.1172/JCI16440. View

Luo L, Gong Y, Qi X, Lai W, Lan H, Luo Y . Effect of tumor suppressor PTEN gene on apoptosis and cell cycle of human airway smooth muscle cells. Mol Cell Biochem. 2013; 375(1-2):1-9. DOI: 10.1007/s11010-012-1484-7. View

Dileepan M, Jude J, Rao S, Walseth T, Panettieri R, Subramanian S . MicroRNA-708 regulates CD38 expression through signaling pathways JNK MAP kinase and PTEN/AKT in human airway smooth muscle cells. Respir Res. 2014; 15:107. PMC: 4156970. DOI: 10.1186/s12931-014-0107-0. View

Ortega-Martinez S . A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front Mol Neurosci. 2015; 8:46. PMC: 4549561. DOI: 10.3389/fnmol.2015.00046. View

Rah S, Kim U . CD38-mediated Ca(2+) signaling contributes to glucagon-induced hepatic gluconeogenesis. Sci Rep. 2015; 5:10741. PMC: 4454144. DOI: 10.1038/srep10741. View

Zhao J, Wang B, Wang X, Shang X . Up-regulation of Ca/CaMKII/CREB signaling in salicylate-induced tinnitus in rats. Mol Cell Biochem. 2018; 448(1-2):71-76. DOI: 10.1007/s11010-018-3314-z. View

10.

Yue J, Wei W, Lam C, Zhao Y, Dong M, Zhang L . CD38/cADPR/Ca2+ pathway promotes cell proliferation and delays nerve growth factor-induced differentiation in PC12 cells. J Biol Chem. 2009; 284(43):29335-42. PMC: 2785564. DOI: 10.1074/jbc.M109.049767. View

11.

Musa N, Ramakrishnan M, Li J, Kartha S, Liu P, Pestell R . Forskolin inhibits cyclin D1 expression in cultured airway smooth-muscle cells. Am J Respir Cell Mol Biol. 1999; 20(2):352-8. DOI: 10.1165/ajrcmb.20.2.3160. View

12.

Hong W, Peng G, Hao B, Liao B, Zhao Z, Zhou Y . Nicotine-Induced Airway Smooth Muscle Cell Proliferation Involves TRPC6-Dependent Calcium Influx Via α7 nAChR. Cell Physiol Biochem. 2017; 43(3):986-1002. DOI: 10.1159/000481651. View

13.

Kim S, Lee Y . PTEN as a unique promising therapeutic target for occupational asthma. Immunopharmacol Immunotoxicol. 2008; 30(4):793-814. DOI: 10.1080/08923970802285164. View

14.

Deshpande D, Guedes A, Lund F, Subramanian S, Walseth T, Kannan M . CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets. Pharmacol Ther. 2016; 172:116-126. PMC: 5346344. DOI: 10.1016/j.pharmthera.2016.12.002. View

15.

Deshpande D, Guedes A, Graeff R, Dogan S, Subramanian S, Walseth T . CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms. Mediators Inflamm. 2018; 2018:8942042. PMC: 5821947. DOI: 10.1155/2018/8942042. View

16.

Lan H, Zhong H, Gao Y, Ren D, Chen L, Zhang D . The PTEN tumor suppressor inhibits human airway smooth muscle cell migration. Int J Mol Med. 2010; 26(6):893-9. DOI: 10.3892/ijmm_00000539. View

17.

Liu Y, Yang K, Shi H, Xu J, Zhang D, Wu Y . MiR-21 modulates human airway smooth muscle cell proliferation and migration in asthma through regulation of PTEN expression. Exp Lung Res. 2015; 41(10):535-45. DOI: 10.3109/01902148.2015.1090501. View

18.

Guedes A, Paulin J, Rivero-Nava L, Kita H, Lund F, Kannan M . CD38-deficient mice have reduced airway hyperresponsiveness following IL-13 challenge. Am J Physiol Lung Cell Mol Physiol. 2006; 291(6):L1286-93. DOI: 10.1152/ajplung.00187.2006. View

19.

Deshpande D, Walseth T, Panettieri R, Kannan M . CD38/cyclic ADP-ribose-mediated Ca2+ signaling contributes to airway smooth muscle hyper-responsiveness. FASEB J. 2003; 17(3):452-4. DOI: 10.1096/fj.02-0450fje. View

20.

Parker T, Wang K, Manning D, Dart C . Soluble adenylyl cyclase links Ca entry to Ca/cAMP-response element binding protein (CREB) activation in vascular smooth muscle. Sci Rep. 2019; 9(1):7317. PMC: 6514005. DOI: 10.1038/s41598-019-43821-3. View