Src-mediated Post-translational Regulation of Endoglin Stability and Function Is Critical for Angiogenesis

• Published in: The Journal of biological chemistry Vol. 289; no. 37; pp. 25486 - 25496
• Main Authors: Pan, Christopher C., Kumar, Sanjay, Shah, Nirav, Hoyt, Dale G., Hawinkels, Lukas J.A.C., Mythreye, Karthikeyan, Lee, Nam Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.09.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Activin Receptors, Type II - genetics; Activin Receptors, Type II - metabolism; Amino Acid Motifs - genetics; Antigens, CD - genetics; Cell Biology; Cell Proliferation - genetics; Endoglin; Endothelial Cells - cytology; Endothelial Cells - metabolism; Humans; Neovascularization, Physiologic - genetics; Phosphorylation; Protein Stability; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptor, Transforming Growth Factor-beta Type II; Receptors, Cell Surface - genetics; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; src-Family Kinases - metabolism; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Tyrosine-Protein Kinase (Tyrosine Kinase); Angiogenesis; Endothelial Cell; Transforming Growth Factor Beta (TGF-β); Vascular Biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.578609

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 (612YIY614) 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 612YIY614 phosphorylation. Interestingly, Src phosphorylation of endoglin-612YIY614 was also an important process for receptor down-regulation by TRACON105 (TRC105), an endoglin-targeting antibody currently in clinical trials. The regulation of 612YIY614 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.