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Cyclin Dependent Kinase 1 (CDK1) Activates Cardiac Fibroblasts via Directly Phosphorylating Paxillin at Ser244.
Int Heart J 2019; 60(2):374-383IH

Abstract

Atrial fibrillation has caused severe burden for people worldwide. Differentiation of fibroblasts into myofibroblasts, and consequent progress in atrial structural remodeling have been considered the basis for persistent atrial fibrillation, yet little is known about the molecular mechanisms underlying the process. Here, we show that cyclin-dependent kinase 1 (CDK1) is activated in atrial fibroblasts from patients with atrial fibrillation (AFPAF) and in platelet derived growth factor BB (PDGF-BB)-treated atrial fibroblasts from patients with sinus rhythm (AFPSR). We also demonstrate that inhibition of CDK1 suppresses fibroblast differentiation and focal adhesion (FA) complex formation. The FA protein paxillin is phosphorylated directly at Ser244 by CDK1. Importantly, transfection of a paxillin construct harboring a Ser to Ala mutation causes FA complex disassembly and greatly inhibits fibroblast activation. AFPSRs applied with a lentiviral vector carrying the shRNA sequence of paxillin dramatically prevents PDGF-BB induced functional activation. Taken together, all these results suggest that phosphorylation of paxillin at Ser244 by CDK1 is a key mechanism in fibroblast differentiation and could eventually assist atrial fibrosis.

Authors+Show Affiliations

Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University.Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University.Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University.Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University.Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University.Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University.Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University.Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University.Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30745530

Citation

Sai, Chen, et al. "Cyclin Dependent Kinase 1 (CDK1) Activates Cardiac Fibroblasts Via Directly Phosphorylating Paxillin at Ser244." International Heart Journal, vol. 60, no. 2, 2019, pp. 374-383.
Sai C, Yunhan J, Zhao J, et al. Cyclin Dependent Kinase 1 (CDK1) Activates Cardiac Fibroblasts via Directly Phosphorylating Paxillin at Ser244. Int Heart J. 2019;60(2):374-383.
Sai, C., Yunhan, J., Zhao, J., Yu, Z., Yun, Z., Zhezhe, C., ... Ruiyan, M. (2019). Cyclin Dependent Kinase 1 (CDK1) Activates Cardiac Fibroblasts via Directly Phosphorylating Paxillin at Ser244. International Heart Journal, 60(2), pp. 374-383. doi:10.1536/ihj.18-073.
Sai C, et al. Cyclin Dependent Kinase 1 (CDK1) Activates Cardiac Fibroblasts Via Directly Phosphorylating Paxillin at Ser244. Int Heart J. 2019 Mar 20;60(2):374-383. PubMed PMID: 30745530.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cyclin Dependent Kinase 1 (CDK1) Activates Cardiac Fibroblasts via Directly Phosphorylating Paxillin at Ser244. AU - Sai,Chen, AU - Yunhan,Jiang, AU - Zhao,Jian, AU - Yu,Zhu, AU - Yun,Zhu, AU - Zhezhe,Cao, AU - Fuqin,Tang, AU - Yingbin,Xiao, AU - Ruiyan,Ma, Y1 - 2019/02/08/ PY - 2019/2/13/pubmed PY - 2019/3/29/medline PY - 2019/2/13/entrez KW - Atrial fibrillation KW - Fibrosis KW - Focal adhesion KW - Platelet derived growth factor BB SP - 374 EP - 383 JF - International heart journal JO - Int Heart J VL - 60 IS - 2 N2 - Atrial fibrillation has caused severe burden for people worldwide. Differentiation of fibroblasts into myofibroblasts, and consequent progress in atrial structural remodeling have been considered the basis for persistent atrial fibrillation, yet little is known about the molecular mechanisms underlying the process. Here, we show that cyclin-dependent kinase 1 (CDK1) is activated in atrial fibroblasts from patients with atrial fibrillation (AFPAF) and in platelet derived growth factor BB (PDGF-BB)-treated atrial fibroblasts from patients with sinus rhythm (AFPSR). We also demonstrate that inhibition of CDK1 suppresses fibroblast differentiation and focal adhesion (FA) complex formation. The FA protein paxillin is phosphorylated directly at Ser244 by CDK1. Importantly, transfection of a paxillin construct harboring a Ser to Ala mutation causes FA complex disassembly and greatly inhibits fibroblast activation. AFPSRs applied with a lentiviral vector carrying the shRNA sequence of paxillin dramatically prevents PDGF-BB induced functional activation. Taken together, all these results suggest that phosphorylation of paxillin at Ser244 by CDK1 is a key mechanism in fibroblast differentiation and could eventually assist atrial fibrosis. SN - 1349-3299 UR - https://www.unboundmedicine.com/medline/citation/30745530/Cyclin_Dependent_Kinase_1_(CDK1)_Activates_Cardiac_Fibroblasts_via_Directly_Phosphorylating_Paxillin_at_Ser244 L2 - https://dx.doi.org/10.1536/ihj.18-073 DB - PRIME DP - Unbound Medicine ER -