βIV-spectrin as a stalk cell-intrinsic regulator of VEGF signaling
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
MetadataShow full item record
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.
RightsCopyright © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
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).
NoteOpen access journal
VersionFinal published version
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.
- Ca(2+)/calmodulin kinase II-dependent regulation of β(IV)-spectrin modulates cardiac fibroblast gene expression, proliferation, and contractility.
- Authors: Nassal DM, Patel NJ, Unudurthi SD, Shaheen R, Yu J, Mohler PJ, Hund TJ
- Issue date: 2021 Jul
- βIV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells.
- Authors: Kline CF, Wright PJ, Koval OM, Zmuda EJ, Johnson BL, Anderson ME, Hai T, Hund TJ, Mohler PJ
- Issue date: 2013 Oct 22
- βIV-Spectrin regulates STAT3 targeting to tune cardiac response to pressure overload.
- Authors: Unudurthi SD, Nassal D, Greer-Short A, Patel N, Howard T, Xu X, Onal B, Satroplus T, Hong D, Lane C, Dalic A, Koenig SN, Lehnig AC, Baer LA, Musa H, Stanford KI, Smith S, Mohler PJ, Hund TJ
- Issue date: 2018 Dec 3
- STAT3: a link between CaMKII-βIV-spectrin and maladaptive remodeling?
- Authors: Hulsurkar M, Quick AP, Wehrens XH
- Issue date: 2018 Dec 3
- Decreased Expression of Vascular Endothelial Growth Factor Receptor 1 Contributes to the Pathogenesis of Hereditary Hemorrhagic Telangiectasia Type 2.
- Authors: Thalgott JH, Dos-Santos-Luis D, Hosman AE, Martin S, Lamandé N, Bracquart D, Srun S, Galaris G, de Boer HC, Tual-Chalot S, Kroon S, Arthur HM, Cao Y, Snijder RJ, Disch F, Mager JJ, Rabelink TJ, Mummery CL, Raymond K, Lebrin F
- Issue date: 2018 Dec 4