βIV-spectrin as a stalk cell-intrinsic regulator of VEGF signaling
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AffiliationDepartment of Pharmacology, University of Arizona
Department of Chemistry & Biochemistry, University of Arizona
BIO5 Institute, University of Arizona
Department of Internal Medicine, University of Arizona
Cancer Center, University of Arizona
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CitationKwak, E.-A., Pan, C. C., Ramonett, A., Kumar, S., Cruz-Flores, P., Ahmed, T., Ortiz, H. R., Lochhead, J. J., Ellis, N. A., Mouneimne, G., Georgieva, T. G., Lee, Y. S., Vanderah, T. W., Largent-Milnes, T., Mohler, P. J., Hund, T. J., Langlais, P. R., Mythreye, K., & Lee, N. Y. (2022). ΒIV-spectrin as a stalk cell-intrinsic regulator of VEGF signaling. Nature Communications.
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AbstractDefective angiogenesis underlies over 50 malignant, ischemic and inflammatory disorders yet long-term therapeutic applications inevitably fail, thus highlighting the need for greater understanding of the vast crosstalk and compensatory mechanisms. Based on proteomic profiling of angiogenic endothelial components, here we report βIV-spectrin, a non-erythrocytic cytoskeletal protein, as a critical regulator of sprouting angiogenesis. Early loss of endothelial-specific βIV-spectrin promotes embryonic lethality in mice due to hypervascularization and hemorrhagic defects whereas neonatal depletion yields higher vascular density and tip cell populations in developing retina. During sprouting, βIV-spectrin expresses in stalk cells to inhibit their tip cell potential by enhancing VEGFR2 turnover in a manner independent of most cell-fate determining mechanisms. Rather, βIV-spectrin recruits CaMKII to the plasma membrane to directly phosphorylate VEGFR2 at Ser984, a previously undefined phosphoregulatory site that strongly induces VEGFR2 internalization and degradation. These findings support a distinct spectrin-based mechanism of tip-stalk cell specification during vascular development. © 2022, The Author(s).
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Except where otherwise noted, this item's license is described as Copyright © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License.