PXD029682

PXD029682 is an original dataset announced via ProteomeXchange.

Title	CDC-like Kinase 4 Deficiency Contributes to Pathological Cardiac Hypertrophy by Modulating NEXN Phosphorylation
Description	Kinase-catalyzed phosphorylation plays crucial roles in numerous biological processes. CDC-like kinases (CLKs) are a group of evolutionarily conserved dual-specificity kinases that have been implicated in RNA splicing, glucose metabolism, diet-induced thermogenesis and so on. However, it is still largely unknown whether CLKs are involved in pathologic cardiac hypertrophy. This study aimed to investigate the role of CLKs in pathologic cardiac hypertrophy and the underlying mechanisms. Using small RNA interference, we discovered that defects in CLK4, but not CLK1, CLK2 or CLK3, were associated with the pathogenesis of pathological cardiomyocyte hypertrophy, while overexpression of CLK4 exerted resistance to isoproterenol-induced pathological cardiomyocyte hypertrophy. Moreover, the expression of CLK4 was significantly reduced in the failed myocardia of mice subjected to either transverse aortic constriction or isoproterenol infusion. Through the Cre/loxP system, we constructed cardiac-specific Clk4-knockout (Clk4-cKO) mice, which manifested pathological myocardial hypertrophy with progressive left ventricular systolic dysfunction and heart dilation. Phosphoproteomic analysis revealed significant changes in phosphorylation of sarcomere-related proteins in Clk4-cKO mice. Further experiments identified nexilin (NEXN), an F-actin binding protein, as the direct substrate of CLK4, and overexpression of a phosphorylation-mimic mutant of NEXN was sufficient to reverse the hypertrophic growth of cardiomyocytes induced by Clk4 knockdown. Importantly, restoring the phosphorylated NEXN significantly ameliorated the myocardial hypertrophy in Clk4-cKO mice. CLK4 phosphorylates NEXN to regulate the development of pathological cardiac hypertrophy. CLK4 may serve as a potential intervention target for the prevention and treatment of heart failure.
HostingRepository	PRIDE
AnnounceDate	2022-07-05
AnnouncementXML	Submission_2022-07-05_00:31:26.884.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jian Huang
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-11 05:22:44	ID requested
⏵ 1	2022-07-05 00:31:27	announced

Dataset with its publication pending

submitter keyword: CDC-like kinase 4, pathologic cardiac hypertrophy, NEXN, phosphorylation

Yi-Han Chen
contact affiliation	Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China.
contact email	yihanchen@tongji.edu.cn
lab head
Jian Huang
contact affiliation	Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai
contact email	huang_jian126@tongji.edu.cn
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029682
     1. Label: PRIDE project
     2. Name: CDC-like Kinase 4 Deficiency Contributes to Pathological Cardiac Hypertrophy by Modulating NEXN Phosphorylation