|Title||Src-mediated post-translational regulation of endoglin stability and function is critical for angiogenesis.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Pan CC, Kumar S, Shah N, Hoyt DG, Hawinkels LJAC, Mythreye K, Lee NY|
|Journal||J Biol Chem|
|Date Published||2014 Sep 12|
|Keywords||Activin Receptors, Type II, Amino Acid Motifs, Antigens, CD, Cell Proliferation, Endoglin, Endothelial Cells, Humans, Neovascularization, Physiologic, Phosphorylation, Protein Stability, Protein-Serine-Threonine Kinases, Receptors, Cell Surface, Receptors, Transforming Growth Factor beta, src-Family Kinases, Transforming Growth Factor beta|
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.
|Alternate Journal||J. Biol. Chem.|
|PubMed Central ID||PMC4162155|
|Grant List||R01 CA178443 / CA / NCI NIH HHS / United States |
CA178443 / CA / NCI NIH HHS / United States
Src-mediated post-translational regulation of endoglin stability and function is critical for angiogenesis.
Faculty Member Reference:
Nam Lee, Ph.D.