PTK7对内皮细胞KDR活性和血管生成的双相作用。,Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

当前位置： X-MOL 学术 › BBA Mol. Cell Res. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

PTK7对内皮细胞KDR活性和血管生成的双相作用。
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 4.6 ) Pub Date : 2015-05-20 , DOI: 10.1016/j.bbamcr.2015.05.015
Won-Sik Shin ₁ , Hye-Won Na ₁ , Seung-Taek Lee ₁

Affiliation

蛋白酪氨酸激酶7（PTK7）是缺乏催化活性的缺陷受体蛋白酪氨酸激酶家族的成员。在各种癌症中，PTK7的表达均增加，但其在致癌作用中的作用尚不十分清楚。我们先前显示，PTK7功能的破坏会抑制HUVEC和小鼠中VEGF诱导的血管生成表型。在这里，我们研究了通过PTK7调节VEGF诱导的生理效应的分子机制。用高浓度的PTK7胞外域（可溶性PTK7; sPTK7）或PTK7敲低处理可抑制VEGF诱导的激酶插入域受体（KDR）磷酸化，但不抑制fms相关酪氨酸激酶1（FLT-1）的磷酸化。在HUVEC中。在HUVEC和HEK293细胞中，PTK7，更具体地说是sPTK7，与KDR相互作用，但不与FLT-1相互作用。体外结合试验表明，sPTK7形成的寡聚体具有高达约1：3摩尔比的KDR胞外域（sKDR），反之亦然。sPTK7的摩尔比低于sKDR，可增强VEGF与sKDR的结合。在相同或更高的摩尔比下，它减少了VEGF与sKDR的结合。sPTK7浓度的增加或PTK7表达水平的增加先是增加，然后是VEGF诱导的HUVEC的KDR磷酸化，迁移和毛细管样管形成，以及体内血管生成。两者合计，我们的数据表明PTK7通过诱导低浓度的KDR分子低聚和周围高浓度的KDR分子双相调节KDR的活性。

"点击查看英文标题和摘要"

Biphasic effect of PTK7 on KDR activity in endothelial cells and angiogenesis.

Protein tyrosine kinase 7 (PTK7) is a member of the defective receptor protein tyrosine kinase family which lacks catalytic activity. Expression of PTK7 is increased in various cancers but its role in carcinogenesis is not well understood. We previously showed that disruption of PTK7 function suppresses VEGF-induced angiogenic phenotypes in HUVECs and mice. Here, we investigated molecular mechanisms for modulating VEGF-induced physiological effects by PTK7. Treatment with a high concentration of extracellular domain of PTK7 (soluble PTK7; sPTK7) or knockdown of PTK7 inhibited VEGF-induced phosphorylation of kinase insert domain receptor (KDR) but did not inhibit phosphorylation of fms-related tyrosine kinase 1 (FLT-1) in HUVECs. PTK7, more specifically sPTK7, interacted with KDR but not with FLT-1 in HUVECs and HEK293 cells. In vitro binding assay showed that sPTK7 formed oligomers with the extracellular domain of KDR (sKDR) up to an approximately 1:3 molar ratio, and vice versa. sPTK7 at lower molar ratios than sKDR enhanced the binding of VEGF to sKDR. At the same or higher molar ratios, it reduced the binding of VEGF to sKDR. Increasing concentrations of sPTK7 or increasing levels of PTK7 expression first increased and then decreased VEGF-induced KDR phosphorylation, migration, and capillary-like tube formation of HUVECs, as well as in vivo angiogenesis. Taken together, our data demonstrates that PTK7 regulates the activity of KDR biphasically by inducing oligomerization of KDR molecules at lower concentrations and by surrounding KDR molecules at higher concentrations.

更新日期：2019-11-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文