title: PEST motif serine and tyrosine phosphorylation controls vascular endothelial growth factor receptor 2 stability and downregulation.
abstract: The internalization and degradation of vascular endothelial growth factor receptor 2 (VEGFR-2), a potent angiogenic receptor tyrosine kinase, is a central mechanism for the regulation of the coordinated action of VEGF in angiogenesis. Here, we show that VEGFR-2 is ubiquitinated in response to VEGF, and Lys 48-linked polyubiquitination controls its degradation via the 26S proteosome. The degradation and ubiquitination of VEGFR-2 is controlled by its PEST domain, and the phosphorylation of Ser1188/Ser1191 is required for the ubiquitination of VEGFR-2. F-box-containing β-Trcp1 ubiquitin E3 ligase is recruited to S1188/S1191 VEGFR-2 and mediates the ubiquitination and degradation of VEGFR-2. The PEST domain also controls the activation of p38 mitogen-activated protein kinase (MAPK) through phospho-Y1173. The activation of p38 stabilizes VEGFR-2, and its inactivation accelerates VEGFR-2 downregulation. The VEGFR-2-mediated activation of p38 is established through the protein kinase A (PKA)/MKK6 pathway. PKA is recruited to VEGFR-2 through AKAP1/AKAP149, and its phosphorylation requires Y1173 of VEGFR-2. The study has identified a unique mechanism in which VEGFR-2 stability and degradation is modulated. The PEST domain acts as a dual modulator of VEGFR-2; the phosphorylation of S1188/S1191 controls ubiquitination and degradation via β-Trcp1, where the phosphorylation of Y1173 through PKA/p38 MAPK controls the stability of VEGFR-2.
authors.affiliation: Department of Pathology, Boston University Medical Campus, 670 Albany St., Boston, MA 02118, USA.
authors.forename: Rosana D
authors.initials: RD
authors.lastname: Meyer
authors.forename: Srimathi
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Amrik J
authors.initials: AJ
authors.lastname: Singh
authors.forename: John E
authors.initials: JE
authors.lastname: Mahoney
authors.forename: Kobra Rezazadeh
authors.initials: KR
authors.lastname: Gharahassanlou
authors.forename: Nader
authors.initials: N
authors.lastname: Rahimi
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D034741:RNA, Small Interfering; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D014443:Tyrosine / Q000378:metabolism; D054875:Ubiquitination; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; C105137:AKAP1 protein, human; C471644:BTRC protein, human; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D044844:beta-Transducin Repeat-Containing Proteins; D014443:Tyrosine; D012694:Serine; D040301:Vascular Endothelial Growth Factor Receptor-2; D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease