Unknown

Dataset Information

0

Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling.


ABSTRACT: Epsins are a family of ubiquitin-binding, endocytic clathrin adaptors. Mice lacking both epsins 1 and 2 (Epn1/2) die at embryonic day 10 and exhibit an abnormal vascular phenotype. To examine the angiogenic role of endothelial epsins, we generated mice with constitutive or inducible deletion of Epn1/2 in vascular endothelium. These mice exhibited no abnormal phenotypes under normal conditions, suggesting that lack of endothelial epsins 1 and 2 did not affect normal blood vessels. In tumors, however, loss of epsins 1 and 2 resulted in disorganized vasculature, significantly increased vascular permeability, and markedly retarded tumor growth. Mechanistically, we show that VEGF promoted binding of epsin to ubiquitinated VEGFR2. Loss of epsins 1 and 2 specifically impaired endocytosis and degradation of VEGFR2, which resulted in excessive VEGF signaling that compromised tumor vascular function by exacerbating nonproductive leaky angiogenesis. This suggests that tumor vasculature requires a balance in VEGF signaling to provide sufficient productive angiogenesis for tumor development and that endothelial epsins 1 and 2 negatively regulate the output of VEGF signaling. Promotion of excessive VEGF signaling within tumors via a block of epsin 1 and 2 function may represent a strategy to prevent normal angiogenesis in cancer patients who are resistant to anti-VEGF therapies.

SUBMITTER: Pasula S 

PROVIDER: S-EPMC3533553 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications


Epsins are a family of ubiquitin-binding, endocytic clathrin adaptors. Mice lacking both epsins 1 and 2 (Epn1/2) die at embryonic day 10 and exhibit an abnormal vascular phenotype. To examine the angiogenic role of endothelial epsins, we generated mice with constitutive or inducible deletion of Epn1/2 in vascular endothelium. These mice exhibited no abnormal phenotypes under normal conditions, suggesting that lack of endothelial epsins 1 and 2 did not affect normal blood vessels. In tumors, howe  ...[more]

Similar Datasets

| S-EPMC3920663 | biostudies-literature
| S-EPMC3083229 | biostudies-literature
| S-EPMC4665789 | biostudies-literature
| S-EPMC3686817 | biostudies-literature
| 2073020 | ecrin-mdr-crc
| S-EPMC2562899 | biostudies-literature
| S-EPMC2043550 | biostudies-literature
| S-EPMC5719432 | biostudies-literature
| S-EPMC7648028 | biostudies-literature
| S-EPMC5294206 | biostudies-literature