4.7 Article

Identification of VEGFR2 as the Histatin-1 receptor in endothelial cells

期刊

BIOCHEMICAL PHARMACOLOGY
卷 201, 期 -, 页码 -

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2022.115079

关键词

Histatins; Angiogenesis; Vascular endothelial growth factor receptor; Molecular modeling; Protein Binding; Cell migration

资金

  1. National Fund for Scientific and Technological Development (FONDECYT) [1220517, 1180495]
  2. National Agency of Research and Development (ANID) -Millennium Science Initiative Program [ICN09_016/ICN 2021_045]
  3. Advanced Center for Chronic Diseases, FONDAP-ACCDiS [15130011]
  4. FONDECYT [1181361, 1171484]
  5. ANID [21181094]

向作者/读者索取更多资源

In this study, it was found that VEGFR2 is the endothelial cell receptor of Histatin-1, revealing the mechanism by which Histatin-1 promotes endothelial cell migration and angiogenesis.
Histatin-1 is a salivary peptide with antimicrobial and wound healing promoting activities, which was previously shown to stimulate angiogenesis in vitro and in vivo via inducing endothelial cell migration. The mechanisms underlying the proangiogenic effects of Histatin-1 remain poorly understood and specifically, the endothelial receptor for this peptide, is unknown. Based on the similarities between Histatin-1-dependent responses and those induced by the prototypical angiogenic receptor, vascular endothelial growth factor receptor 2 (VEGFR2), we hypothesized that VEGFR2 is the Histatin-1 receptor in endothelial cells. First, we observed that VEGFR2 is necessary for Histatin-1-induced endothelial cell migration, as shown by both pharmacological inhibition studies and siRNA-mediated ablation of VEGFR2. Moreover, Histatin-1 co-immunoprecipitated and co-localized with VEGFR2, associating spatial proximity between these proteins with receptor activation. Indeed, pulldown assays with pure, tagged and non-tagged proteins showed that Histatin-1 and VEGFR2 directly interact in vitro. Optical tweezers experiments permitted estimating kinetic parameters and rupture forces, indicating that the Histatin-1VEGFR2 interaction is transient, but specific and direct. Sequence alignment and molecular modeling identified residues Phe26, Tyr30 and Tyr34 within the C-terminal domain of Histatin-1 as relevant for VEGFR2 binding and activation. This was corroborated by mutation and molecular dynamics analyses, as well as in direct binding assays. Importantly, these residues were required for Histatin-1 to induce endothelial cell migration and angiogenesis in vitro. Taken together, our findings reveal that VEGFR2 is the endothelial cell receptor of Histatin1 and provide insights to the mechanism by which this peptide promotes endothelial cell migration and angiogenesis.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据