BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signaling in angiogenesis

Hidetaka Ohnuki, Hirofumi Inoue, Nobuaki Takemori, Hironao Nakayama, Tomohisa Sakaue, Shinji Fukuda, Daisuke Miwa, Eiji Nishiwaki, Masahiko Hatano, Takeshi Tokuhisa, Yaeta Endo, Masato Nose, Shigeki Higashiyama

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

Angiogenic homeostasis is maintained by a balance between vascular endothelial growth factor (VEGF) and Notch signaling in endothelial cells (ECs). We screened for molecules that might mediate the coupling of VEGF signal transduction with down-regulation of Notch signaling, and identified B-cell chronic lymphocytic leukemia/lymphoma6-associated zinc finger protein (BAZF). BAZF was induced by VEGF-A in ECs to bind to the Notch signaling factor Cpromoter binding factor 1 (CBF1), and to promote the degradation of CBF1 through polyubiquitination in a CBF1-cullin3 (CUL3) E3 ligase complex. BAZF disruption in vivo decreased endothelial tip cell number and filopodia protrusion, and markedly abrogated vascular plexus formation in the mouse retina, overlapping the retinal phenotype seen in response to Notch activation. Further, impaired angiogenesis and capillary remodeling were observed in skin-wounded BAZF-/- mice. We therefore propose that BAZF supports angiogenic sprouting via BAZF-CUL3-based polyubiquitination-dependent degradation of CBF1 to down-regulate Notch signaling.

Original languageEnglish
Pages (from-to)2688-2698
Number of pages11
JournalBlood
Volume119
Issue number11
DOIs
Publication statusPublished - 2012 Mar 15

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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