βIV-spectrin as a stalk cell-intrinsic regulator of VEGF signaling

Eun A. Kwak, Christopher C. Pan, Aaron Ramonett, Sanjay Kumar, Paola Cruz-Flores, Tasmia Ahmed, Hannah R. Ortiz, Jeffrey J. Lochhead, Nathan A. Ellis, Ghassan Mouneimne, Teodora G. Georgieva, Yeon Sun Lee, Todd W. Vanderah, Tally Largent-Milnes, Peter J. Mohler, Thomas J. Hund, Paul R. Langlais, Karthikeyan Mythreye, Nam Y. Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Defective 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.

Original languageEnglish (US)
Article number1326
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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