title: 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.
authors.affiliation: Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Satish
authors.initials: S
authors.lastname: Pasula
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Cai
authors.forename: Yunzhou
authors.initials: Y
authors.lastname: Dong
authors.forename: Mirko
authors.initials: M
authors.lastname: Messa
authors.forename: John
authors.initials: J
authors.lastname: McManus
authors.forename: Baojun
authors.initials: B
authors.lastname: Chang
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Liu
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.forename: Robert Silasi
authors.initials: RS
authors.lastname: Mansat
authors.forename: Seon-Joo
authors.initials: SJ
authors.lastname: Yoon
authors.forename: Scott
authors.initials: S
authors.lastname: Hahn
authors.forename: Jacob
authors.initials: J
authors.lastname: Keeling
authors.forename: Debra
authors.initials: D
authors.lastname: Saunders
authors.forename: Genevieve
authors.initials: G
authors.lastname: Ko
authors.forename: John
authors.initials: J
authors.lastname: Knight
authors.forename: Gail
authors.initials: G
authors.lastname: Newton
authors.forename: Francis
authors.initials: F
authors.lastname: Luscinskas
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Sun
authors.forename: Rheal
authors.initials: R
authors.lastname: Towner
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: Ottavio
authors.initials: O
authors.lastname: Cremona
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
authors.forename: Wang
authors.initials: W
authors.lastname: Min
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D002199:Capillary Permeability; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D004705:Endocytosis; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D015398:Signal Transduction; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C577774:Epn2 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C114154:epsin; C467480:vascular endothelial growth factor A, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2