更新于：2024-11-01

PTP1B x ELA2

更新于：2024-11-01

基本信息

关联

项与 PTP1B x ELA2 相关的药物

PTP1B inhibitors(Dalian University Of Technology/Second Military Medical University PLA/North China Pharmaceutical Group Corp )

靶点

ELA2 x PTP1B

作用机制

ELA2抑制剂 [+1]

在研机构

大连理工大学产业投资有限公司 [+3]

原研机构

大连理工大学产业投资有限公司

在研适应症

炎症 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PTP1B x ELA2 相关的临床结果

登录后查看更多信息

100 项与 PTP1B x ELA2 相关的转化医学

登录后查看更多信息

0 项与 PTP1B x ELA2 相关的专利（医药）

登录后查看更多信息

项与 PTP1B x ELA2 相关的文献（医药）

2024-05-10·Circulation Research

Endothelial PTP1B Deletion Promotes VWF Exocytosis and Venous Thromboinflammation

Article

作者: Poncelet, Philippe ; Dubois, Christophe ; Gogiraju, Rajinikanth ; Münzel, Thomas ; Pedrosa, Denise ; Zifkos, Konstantinos ; Schäfer, Katrin ; Ruf, Wolfram ; Robert, Stéphane ; Reinhardt, Christoph ; Mahfoud, Felix ; Kiouptsi, Klytaimnistra ; Bochenek, Magdalena L ; Panicot-Dubois, Laurence ; Moiko, Kateryna ; Wagner, Mathias

BACKGROUND:Endothelial activation promotes the release of procoagulant extracellular vesicles and inflammatory mediators from specialized storage granules. Endothelial membrane exocytosis is controlled by phosphorylation. We hypothesized that the absence of PTP1B (protein tyrosine phosphatase 1B) in endothelial cells promotes venous thromboinflammation by triggering endothelial membrane fusion and exocytosis.METHODS:Mice with inducible endothelial deletion of PTP1B (End.PTP1B-KO) underwent inferior vena cava ligation to induce stenosis and venous thrombosis. Primary endothelial cells from transgenic mice and human umbilical vein endothelial cells were used for mechanistic studies.RESULTS: Vascular ultrasound and histology showed significantly larger venous thrombi containing higher numbers of Ly6G (lymphocyte antigen 6 family member G)-positive neutrophils in mice with endothelial PTP1B deletion, and intravital microscopy confirmed the more pronounced neutrophil recruitment following inferior vena cava ligation. RT 2 PCR profiler array and immunocytochemistry analysis revealed increased endothelial activation and adhesion molecule expression in primary End.PTP1B-KO endothelial cells, including CD62P (P-selectin) and VWF (von Willebrand factor). Pretreatment with the NF-κB (nuclear factor kappa B) kinase inhibitor BAY11-7082, antibodies neutralizing CD162 (P-selectin glycoprotein ligand-1) or VWF, or arginylglycylaspartic acid integrin-blocking peptides abolished the neutrophil adhesion to End.PTP1B-KO endothelial cells in vitro. Circulating levels of annexin V + procoagulant endothelial CD62E + (E-selectin) and neutrophil (Ly6G + ) extracellular vesicles were also elevated in End.PTP1B-KO mice after inferior vena cava ligation. Higher plasma MPO (myeloperoxidase) and Cit-H3 (citrullinated histone-3) levels and neutrophil elastase activity indicated neutrophil activation and extracellular trap formation. Infusion of End.PTP1B-KO extracellular vesicles into C57BL/6J wild-type mice most prominently enhanced the recruitment of endogenous neutrophils, and this response was blunted in VWF-deficient mice or by VWF-blocking antibodies. Reduced PTP1B binding and tyrosine dephosphorylation of SNAP23 (synaptosome-associated protein 23) resulting in increased VWF exocytosis and neutrophil adhesion were identified as mechanisms, all of which could be restored by NF-κB kinase inhibition using BAY11-7082. CONCLUSIONS:Our findings show that endothelial PTP1B deletion promotes venous thromboinflammation by enhancing SNAP23 phosphorylation, endothelial VWF exocytosis, and neutrophil recruitment.

2015-12-01·Free Radical Biology and Medicine2区 · 医学

4-Hydroxynonenal activates Src through a non-canonical pathway that involves EGFR/PTP1B

2区 · 医学

Article

作者: Forman, Henry Jay ; Zhang, Hongqiao

Src, a non-receptor protein tyrosine kinase involved in many biological processes, can be activated through both redox-dependent and independent mechanisms. 4-Hydroxy-2-nonenal (HNE) is a lipid peroxidation product that is increased in pathophysiological conditions associated with Src activation. This study examined how HNE activates human c-Src. In the canonical pathway Src activation is initiated by dephosphorylation of pTyr530 followed by conformational change that causes Src auto-phosphorylation at Tyr419 and its activation. HNE increased Src activation in both dose- and time-dependent manner, while it also increased Src phosphorylation at Tyr530 (pTyr530 Src), suggesting that HNE activated Src via a non-canonical mechanism. Protein tyrosine phosphatase 1B inhibitor (539741), at concentrations that increased basal pTyr530 Src, also increased basal Src activity and significantly reduced HNE-mediated Src activation. The EGFR inhibitor, AG1478, and EGFR silencing, abrogated HNE-mediated EGFR activation and inhibited basal and HNE-induced Src activity. In addition, AG1478 also eliminated the increase of basal Src activation by a PTP1B inhibitor. Taken together these data suggest that HNE can activate Src partly through a non-canonical pathway involving activation of EGFR and inhibition of PTP1B.