title: G-Protein-Coupled Receptor-2-Interacting Protein-1 Controls Stalk Cell Fate by Inhibiting Delta-like 4-Notch1 Signaling.
abstract: The spatiotemporal localization and expression of Dll4 are critical for sprouting angiogenesis. However, the related mechanisms are poorly understood. Here, we show that G-protein-coupled receptor-kinase interacting protein-1 (GIT1) is a robust endogenous inhibitor of Dll4-Notch1 signaling that specifically controls stalk cell fate. GIT1 is highly expressed in stalk cells but not in tip cells. GIT1 deficiency remarkably enhances Dll4 expression and Notch1 signaling, resulting in impaired retinal sprouting angiogenesis, which can be rescued by treatment with the Notch inhibitor or Dll4 neutralizing antibody. Notch1 regulates Dll4 expression by binding to recombining binding protein suppressor of hairless (RBP-J, a transcriptional regulator of Notch) via a highly conserved ankyrin (ANK) repeat domain. We show that GIT1, which also contains an ANK domain, inhibits the Notch1-Dll4 signaling pathway by competing with Notch1 ANK domain for binding to RBP-J in stalk cells.
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Syamantak
authors.initials: S
authors.lastname: Majumder
authors.affiliation: Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: GuoFu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Xiangbin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Senchanthisai
authors.affiliation: Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Xue
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Coia
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Zhaoqiang
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Smolock
authors.affiliation: Flaum Eye Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA; Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. Electronic address: jinjiang_pang@urmc.rochester.edu.
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Pang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics*; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C485647:GIT1 protein, human; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497570:RBPJ protein, human; D051881:Receptor, Notch1; C064045:delta protein
keywords: Delta-like 4; G-protein-coupled receptor-2-interacting protein1; stalk cell fate