title: Regulation of vascular endothelial growth factor receptor function in angiogenesis by numb and numb-like.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF) signaling is a major regulator of physiological and pathological angiogenesis. VEGF receptor activity is strongly controlled by endocytosis, which can terminate or enhance signal transduction in the angiogenic endothelium, but the exact molecular regulation of these processes remains incompletely understood. We have therefore examined the function of Numb family clathrin-associated sorting proteins in angiogenesis.
  
  
  RESULTS
  We show that Numb proteins are expressed by endothelial cells during retinal angiogenesis in mice. Inducible inactivation of the Numb/Numbl genes in the postnatal endothelium led to impaired vessel growth, reduced endothelial proliferation and sprouting, and decreased VEGF receptor activation. Biochemistry and cell biology experiments established that Numb can interact with VEGFR2 and VEGFR3 and controls VEGF receptor activation in response to ligand stimulation. Experiments in cultured endothelial cells showed that Numb proteins counteract VEGF receptor degradation and promote VEGFR2 recycling back to the plasma membrane.
  
  
  CONCLUSIONS
  Numb proteins control VEGF receptor endocytosis, signaling, and recycling in endothelial cells, which promotes the angiogenic growth of blood vessels.
authors.affiliation: From the Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Münster, Germany (M.v.L., M.N., K. Kato, J.M.K., R.H.A.); and Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, Nagoya, Japan (K. Kato, K. Kaibuchi).
authors.forename: Max
authors.initials: M
authors.lastname: van Lessen
authors.affiliation: From the Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Münster, Germany (M.v.L., M.N., K. Kato, J.M.K., R.H.A.); and Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, Nagoya, Japan (K. Kato, K. Kaibuchi).
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: From the Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Münster, Germany (M.v.L., M.N., K. Kato, J.M.K., R.H.A.); and Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, Nagoya, Japan (K. Kato, K. Kaibuchi).
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kato
authors.affiliation: From the Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Münster, Germany (M.v.L., M.N., K. Kato, J.M.K., R.H.A.); and Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, Nagoya, Japan (K. Kato, K. Kaibuchi).
authors.forename: Jung Mo
authors.initials: JM
authors.lastname: Kim
authors.affiliation: From the Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Münster, Germany (M.v.L., M.N., K. Kato, J.M.K., R.H.A.); and Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, Nagoya, Japan (K. Kato, K. Kaibuchi).
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.affiliation: From the Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Münster, Faculty of Medicine, Münster, Germany (M.v.L., M.N., K. Kato, J.M.K., R.H.A.); and Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, Nagoya, Japan (K. Kato, K. Kaibuchi). ralf.adams@mpi-muenster.mpg.de.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction; D014162:Transfection
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C530266:NUMBL protein, human; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; C106293:Numb protein, mouse; C106292:Numbl protein, mouse; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: VEGF signaling; VEGFR2; angiogenesis; endocytosis; endothelial cell; endothelial cell sprouting and proliferation