缺陷的因子 XII 导致遗传性血管性水肿
中文名称
通路描述
遗传性血管性水肿（HAE）是一种罕见且危及生命的遗传性水肿疾病，其特征是皮肤或胃肠道黏膜或上呼吸道的局部水肿反复发作。HAE 患者水肿的形成主要由于高分子量激肽原（HK）中未受控制的因子 XII（FXII）依赖性激肽系统（KKS）激活导致短暂增加的缓激肽释放。由缓激肽引起的血管性水肿通常与 SERPING1（C1-INH）缺乏有关。SERPING1 是接触系统的调节蛋白。较少情况下，HAE 发生在 SERPING1 活性正常的个体中，并与 FXII、纤溶原和血管生成素等蛋白中的突变有关。在 FXII 脯氨酸富集区第 328 位缬氨酸被替换为赖氨酸或精氨酸（T328K 或 T328R）的几种家庭中已鉴定出该突变。FXII T328K 或 T328R 变体改变了蛋白糖基化并引入了一个新的位点，该位点对纤溶和凝血蛋白酶（如纤溶酶、凝血酶或 FXIa）的酶切敏感。截短的 FXII（329-615，也称为δFXII）将前激肽转化为激肽的能力大于 FXII，导致在相互激活早期产生更多的激肽。其次，FXII（329-615）是比 FXII 更好的激肽底物。截短的 FXII（329-615）引起的激肽/FXII 激活加速，似乎超过了 SERPING1 在正常血浆水平上的调节功能，导致未受控的缓激肽形成。缓激肽与缓激肽 B2 受体（B2R）结合，激活各种促炎信号通路，增加血管通透性和液体外流。由于 FXII 依赖性 KKS 未受控激活导致的过量缓激肽形成，导致毛细血管后静脉处血管通透性增加，从而引起 HAE。
英文描述
NOTCH3 Activation and Transmission of Signal to the Nucleus NOTCH3 receptor can be activated by DLL/JAG ligands DLL1, JAG1, and JAG2 (Shimizu et al. 2000), as well as DLL4 (Claxton and Fruttiger 2004, Indraccolo et al. 2009). Ligand binding induces a conformational change in NOTCH3, which exposes the S2 site in the extracellular region of NOTCH3. The S2 site is cleaved by ADAM10 metalloprotease, generating the membrane anchored NOTCH3 fragment NEXT3. The NEXT3 fragment of NOTCH3 is further cleaved at the S3 site by the gamma secretase complex, releasing the intracellular domain NICD3 into the cytosol (Groot et al. 2014). Besides DLL/JAG ligands, NOTCH3 signaling can also be activated by binding of NOTCH3 to YBX1 (YB 1) (Rauen et al. 2009). NICD3 traffics to the nucleus where it acts as a transcription factor. WWP2, an E3 ubiquitin ligase, negatively regulates NOTCH3 signaling by ubiquitinating NEXT3 and NICD3 in the cytosol and targeting them for lysosome-mediated degradation (Jung et al. 2014). NOTCH3 signaling is also negatively regulated by binding to TACC3 (Bargo et al. 2010) and by EGFR-mediated phosphorylation (Arasada et al. 2014).
所含基因
26 个基因