Protein tyrosine phosphatase PTPN22 negatively modulates platelet function and thrombus formation.,Blood

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Protein tyrosine phosphatase PTPN22 negatively modulates platelet function and thrombus formation.
Blood ( IF 21.0 ) Pub Date : 2022-09-01 , DOI: 10.1182/blood.2022015554
Xiamin Wang _{1,

2,

3} , Guangyu Wei _{1,

2,

3} , Yangyang Ding _{1,

2,

3} , Xiang Gui _{1,

2,

3} , Huan Tong _{1,

2,

3} , Xiaoqi Xu _{1,

2,

3} , Sixuan Zhang _{1,

2,

3} , Zengtian Sun _{1,

2,

3} , Wen Ju _{1,

2,

3} , Yue Li ₄ , Ruosi Yao _{1,

2,

3} , Qingyu Wu _{1,

2,

3} , Zhihao Lu ₅ , Chunling Fu _{1,

2,

3} , Zhenyu Li _{1,

2,

3} , Si Zhang ₆ , Elizabeth E Gardiner ₇ , Robert K Andrews ₇ , Hu Hu ₈ , Lingyu Zeng _{1,

2,

3,

4} , Kailin Xu _{1,

2,

3} , Jianlin Qiao _{1,

2,

3}

Affiliation

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a protein tyrosine phosphatase that negatively regulates T-cell signaling. However, whether it is expressed and functions in platelets remains unknown. Here we investigated the expression and role of PTPN22 in platelet function. We reported PTPN22 expression in both human and mouse platelets. Using PTPN22-/- mice, we showed that PTPN22 deficiency significantly shortened tail-bleeding time and accelerated arterial thrombus formation without affecting venous thrombosis and the coagulation factors VIII and IX. Consistently, PTPN22-deficient platelets exhibited enhanced platelet aggregation, granule secretion, calcium mobilization, lamellipodia formation, spreading, and clot retraction. Quantitative phosphoproteomic analysis revealed the significant difference of phosphodiesterase 5A (PDE5A) phosphorylation in PTPN22-deficient platelets compared with wild-type platelets after collagen-related peptide stimulation, which was confirmed by increased PDE5A phosphorylation (Ser92) in collagen-related peptide-treated PTPN22-deficient platelets, concomitant with reduced level and vasodilator-stimulated phosphoprotein phosphorylation (Ser157/239). In addition, PTPN22 interacted with phosphorylated PDE5A (Ser92) and dephosphorylated it in activated platelets. Moreover, purified PTPN22 but not the mutant form (C227S) possesses intrinsic serine phosphatase activity. Furthermore, inhibition of PTPN22 enhanced human platelet aggregation, spreading, clot retraction, and increased PDE5A phosphorylation (Ser92). In conclusion, our study shows a novel role of PTPN22 in platelet function and arterial thrombosis, identifying new potential targets for future prevention of thrombotic or cardiovascular diseases.

中文翻译：

蛋白酪氨酸磷酸酶 PTPN22 负向调节血小板功能和血栓形成。

22 型蛋白酪氨酸磷酸酶非受体 (PTPN22) 是一种蛋白酪氨酸磷酸酶，可负向调节 T 细胞信号。然而，它是否在血小板中表达和发挥作用仍然未知。在这里，我们研究了 PTPN22 在血小板功能中的表达和作用。我们报告了 PTPN22 在人和小鼠血小板中的表达。使用 PTPN22-/- 小鼠，我们发现 PTPN22 缺陷显着缩短尾部出血时间并加速动脉血栓形成，而不影响静脉血栓形成和凝血因子 VIII 和 IX。一致地，PTPN22 缺陷的血小板表现出增强的血小板聚集、颗粒分泌、钙动员、片状伪足形成、扩散和凝块回缩。定量磷酸化蛋白质组学分析显示，在胶原相关肽刺激后，PTPN22 缺陷型血小板中的磷酸二酯酶 5A (PDE5A) 磷酸化与野生型血小板相比存在显着差异，这通过胶原相关肽处理的 PTPN22 中 PDE5A 磷酸化 (Ser92) 增加得到证实- 血小板缺陷，伴有水平降低和血管扩张剂刺激的磷蛋白磷酸化 (Ser157/239)。此外，PTPN22 与磷酸化的 PDE5A (Ser92) 相互作用并使其在活化的血小板中去磷酸化。此外，纯化的 PTPN22 而不是突变形式 (C227S) 具有内在的丝氨酸磷酸酶活性。此外，抑制 PTPN22 可增强人血小板聚集、扩散、凝块回缩，并增加 PDE5A 磷酸化 (Ser92)。综上所述，

更新日期：2022-06-29

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