title: Identification of PDCL3 as a novel chaperone protein involved in the generation of functional VEGF receptor 2.
abstract: Angiogenesis, a hallmark step in tumor metastasis and ocular neovascularization, is driven primarily by the function of VEGF ligand on one of its receptors, VEGF receptor 2 (VEGFR-2). Central to the proliferation and ensuing angiogenesis of endothelial cells, the abundance of VEGFR-2 on the surface of endothelial cells is essential for VEGF to recognize and activate VEGFR-2. We have identified phosducin-like 3 (PDCL3, also known as PhLP2A), through a yeast two-hybrid system, as a novel protein involved in the stabilization of VEGFR-2 by serving as a chaperone. PDCL3 binds to the juxtamembrane domain of VEGFR-2 and controls the abundance of VEGFR-2 by inhibiting its ubiquitination and degradation. PDCL3 increases VEGF-induced tyrosine phosphorylation and is required for VEGFR-2-dependent endothelial capillary tube formation and proliferation. Taken together, our data provide strong evidence for the role of PDCL3 in angiogenesis and establishes the molecular mechanism by which it regulates VEGFR-2 expression and function.
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Srimathi
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Rosana D
authors.initials: RD
authors.lastname: Meyer
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lugo
authors.forename: Nader
authors.initials: N
authors.lastname: Rahimi
mesh_terms: D000818:Animals; D002196:Capillaries / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012441:Saccharomyces cerevisiae; D013552:Swine; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; C498322:PDCL3 protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Cell Biology; Cell Signaling; Receptor Regulation; Ubiquitination; Vascular Endothelial Growth Factor (VEGF)