Arizona Health Sciences

Src-mediated post-translational regulation of endoglin stability and function is critical for angiogenesis.

TitleSrc-mediated post-translational regulation of endoglin stability and function is critical for angiogenesis.
Publication TypeJournal Article
Year of Publication2014
AuthorsPan CC, Kumar S, Shah N, Hoyt DG, Hawinkels LJAC, Mythreye K, Lee NY
JournalJ Biol Chem
Volume289
Issue37
Pagination25486-96
Date Published2014 Sep 12
ISSN1083-351X
KeywordsActivin 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
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.

DOI10.1074/jbc.M114.578609
Alternate JournalJ. Biol. Chem.
PubMed ID25070888
PubMed Central IDPMC4162155
Grant ListR01 CA178443 / CA / NCI NIH HHS / United States
CA178443 / CA / NCI NIH HHS / United States
Faculty Member Reference: 
Nam Lee, Ph.D.