title: Src-mediated post-translational regulation of endoglin stability and function is critical for angiogenesis.
abstract: Endoglin is a transforming growth factor β (TGF-β) co-receptor essential for angiogenesis and tumor vascularization. Endoglin modulates the crucial balance between pro- and anti-angiogenic signaling by activin receptor-like kinase (ALK) 1, 5, and TGF-β type II (TβRII) receptors. Despite its established role in physiology and disease, the mechanism of endoglin down-regulation remains unknown. Here we report that the conserved juxtamembrane cytoplasmic tyrosine motif ((612)YIY(614)) is a critical determinant of angiogenesis. Src directly phosphorylates this motif to induce endoglin internalization and degradation via the lysosome. We identified epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) as Src-activators that induce endoglin turnover following (612)YIY(614) phosphorylation. Interestingly, Src phosphorylation of endoglin-(612)YIY(614) was also an important process for receptor down-regulation by TRACON105 (TRC105), an endoglin-targeting antibody currently in clinical trials. The regulation of (612)YIY(614) phosphorylation was critical for angiogenesis, as both the phosphomimetic and unphosphorylatable mutants impaired endothelial functions including proliferation, migration, and capillary tube formation. Collectively, these findings establish Src and pro-angiogenic mitogens as critical mediators of endoglin stability and function.
authors: From the Division of Pharmacology, College of Pharmacy, and.
authors: Christopher C
authors: CC
authors: Pan
authors: From the Division of Pharmacology, College of Pharmacy, and.
authors: Sanjay
authors: S
authors: Kumar
authors: From the Division of Pharmacology, College of Pharmacy, and.
authors: Nirav
authors: N
authors: Shah
authors: From the Division of Pharmacology, College of Pharmacy, and.
authors: Dale G
authors: DG
authors: Hoyt
authors: the Department of Molecular Cell Biology, Leiden University Medical Center, Leiden University, 2333 Leiden, the Netherlands.
authors: Lukas J A C
authors: LJ
authors: Hawinkels
authors: the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, and.
authors: Karthikeyan
authors: K
authors: Mythreye
authors: From the Division of Pharmacology, College of Pharmacy, and Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio 43210, lee.5064@osu.edu.
authors: Nam Y
authors: NY
authors: Lee
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs / Q000235:genetics*; D015703:Antigens, CD / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D000071063:Endoglin; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D000077294:Receptor, Transforming Growth Factor-beta Type II; D011956:Receptors, Cell Surface / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Angiogenesis; Endothelial Cell; Transforming Growth Factor Beta (TGF-β); Tyrosine-Protein Kinase (Tyrosine Kinase); Vascular Biology