title: Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis.
abstract: Expression and activation of vascular endothelial growth factor receptor 2 (VEGFR-2) by VEGF ligands are the main events in the stimulation of pathological angiogenesis. VEGFR-2 expression is generally low in the healthy adult blood vessels, but its expression is markedly increased in the pathological angiogenesis. In this report, we demonstrate that phosducin-like 3 (PDCL3), a recently identified chaperone protein involved in the regulation of VEGFR-2 expression, is required for angiogenesis in zebrafish and mouse. PDCL3 undergoes N-terminal methionine acetylation, and this modification affects PDCL3 expression and its interaction with VEGFR-2. Expression of PDCL3 is regulated by hypoxia, the known stimulator of angiogenesis. The mutant PDCL3 that is unable to undergo N-terminal methionine acetylation was refractory to the effect of hypoxia. The siRNA-mediated silencing of PDCL3 decreased VEGFR-2 expression resulting in a decrease in VEGF-induced VEGFR-2 phosphorylation, whereas PDCL3 over-expression increased VEGFR-2 protein. Furthermore, we show that PDCL3 protects VEGFR-2 from misfolding and aggregation. The data provide new insights for the chaperone function of PDCL3 in angiogenesis and the roles of hypoxia and N-terminal methionine acetylation in PDCL3 expression and its effect on VEGFR-2.
authors.affiliation: Departments of Pathology and Ophthalmology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Srimathi
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Renal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Vipul
authors.initials: V
authors.lastname: Chitalia
authors.affiliation: Departments of Pathology and Ophthalmology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Rosana D
authors.initials: RD
authors.lastname: Meyer
authors.affiliation: Departments of Pathology and Ophthalmology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Hartsough
authors.affiliation: Departments of Pathology and Ophthalmology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Mehta
authors.affiliation: Section of Hematology and Medical Oncology, Department of Pharmacology and Experimental Therapeutics, The Center for Cancer Research, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Itrat
authors.initials: I
authors.lastname: Harrold
authors.affiliation: Section of Hematology and Medical Oncology, Department of Pharmacology and Experimental Therapeutics, The Center for Cancer Research, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Anderson
authors.affiliation: Section of Hematology and Medical Oncology, Department of Pharmacology and Experimental Therapeutics, The Center for Cancer Research, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
authors.affiliation: Department of Biochemistry and Center for Biomedical Mass Spectrometry, School of Medicine, Boston University Medical Campus, Boston, MA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Center for Biomedical Mass Spectrometry, School of Medicine, Boston University Medical Campus, Boston, MA, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Costello
authors.affiliation: Departments of Pathology and Ophthalmology, Boston University School of Medicine, Boston, MA, 02118, USA. nrahimi@bu.edu.|Department of Pathology, Boston University Medical Campus, 670 Albany St., Room 510, Boston, MA, 02118, USA. nrahimi@bu.edu.
authors.forename: Nader
authors.initials: N
authors.lastname: Rahimi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017510:Protein Folding; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis*
chemical_list: D002352:Carrier Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; C498322:PDCL3 protein, human; C000588866:KDR protein, human; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Chaperone protein; Hypoxia; N-terminal methionine acetylation; PDCL3; Protein ubiquitination; VEGFR-2