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PTPN14通过增强光滑肌肉细胞中的PDGFRβ信号传递来加剧新极端增生症

Qiannan Ma^1,2, Xue He¹, Xue Wang¹

¹Tianjin Key Laboratory of Metabolic Diseases, Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China.

Nature communications

|August 27, 2024

概括

蛋白氨酸酸酶非受体14型 (PTPN14) 在心血管疾病中促进光滑肌肉细胞调节. PTPN14在Y692处去酸化PDGFRβ,抑制其信号传递并减少新极端增生.

科学领域:

心血管生物学心血管生物学
细胞信号传递细胞信号传递
疾病的分子机制.

背景情况:

光滑肌细胞 (SMC) 的表型调制是闭塞性心血管疾病的核心.
血小板衍生生长因子受体β (PDGFRβ) 信号驱动SMC调制.
对于PDGFRβ和14型非受体蛋白氨酸酸酶 (PTPN14) 的调节作用,在新极度增生症中尚不完全理解.

研究的目的:

研究PTPN14在调节PDGFRβ信号和SMC表型调制中的作用.
阐明PTPN14影响新极端增生症的机制.
确定PTPN14和PDGFRβ酸化在人类冠状动脉疾病中的临床相关性.

主要方法:

在新极端增生期间,对SMC中PTPN14表达的分析.
使用PTPN14过度表达和SMC特定的淘汰赛小鼠模型.
执行RNA测序 (RNA-seq) 来评估信号通路的变化.
使用生物化学测试研究PTPN14和PDGFRβ之间的相互作用.
与人类冠状动脉狭窄相关的PTPN14和-PDGFRβ^Y692水平.

主要成果:

在新极端增生症期间,PTPN14在SMC上升调节,并加剧了这种情况.
特定于SMC的PTPN14缺陷可以缓解新极致增生症.
PTPN14与PDGFRβ相互作用,在Y692位点中介解化.
PDGFRβ^Y692的酸化对PDGFRβ信号进行负面调节.
PTPN14缺乏抑制PDGFRβ信号诱导的SMC表型调制.
PTPN14和-PDGFRβ^Y692水平与人类冠状动脉狭窄相关.

结论:

通过调节SMC表型,PTPN14是新极度增生症的关键促进体.
PTPN14在Y692处去化PDGFRβ,而Y692处是PDGFRβ信号传递的自我抑制位点.
针对PTPN14可能为闭塞性心血管疾病提供治疗策略.

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