Title:
CUL3-based Ub E3 ligase; a key modulator in vascular endothelial cell function and angiogenesis

 

Speaker:
Shigeki Higashiyama, Ph.D.
Department of Cell Growth and Tumor Regulation,
Proteo-Science Center (PROS), Ehime University
Department of Biochemistry and Molecular Genetics,
Ehime University Graduate School of Medicine
shigeki@m.ehime-u.ac.jp

 

Abstract:
Angiogenesis is the process of new microvascular formation from pre-existing vessels. In adult, homeostasis of angiogenesis is maintained on the balance between pro- and anti-angiogenic signaling. “Out of the balance” causes abnormal angiogenesis, which is linked to more than 70 diseases, affecting ~1 billion people, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, psoriasis, etc. in excessive angiogenesis, and coronary artery disease, stroke, and chronic wounds, etc. in insufficient angiogenesis. Therefore, it is crucial to understand the molecular mechanism underlining “balancing between pro- and anti-angiogenic signaling” for establishing novel therapeutic strategies. We recently identified a Cullin 3 (CUL3)-based ubiquitin (Ub) ligase complex, CUL3-BAZF-CBF1, which is a key player to break the balance between VEGF (pro-angiogenic) and Notch (anti-angiogenic) signaling. In this seminar, I will present the multiple roles of CUL3-besed Ub ligase complexes in endothelial cells and angiogenesis, and our technical approaches based on a 20K protein array originally made in our center.

 

References:
1.Ohnuki H, Inoue H, Takemori N, Nakayama H, Sakaue T, Fukuda S, Miwa D, Nishiwaki E, Hatano M, Tokuhisa T, Endo Y, Nose M, Higashiyama S. BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signaling in angiogenesis. Blood 119, 2688-98, 2012.
2.Sakaue T, Sakakibara I, Uesugi T, Fujisaki A, Nakashiro KI, Hamakawa H, Kubota E, Joh T, Imai YK, Izutani H, Higashiyama S. The CUL3-SPOP-DAXX axis is a novel regulator of VEGFR2 expression in vascular endothelial cells. Sci Rep. 7, 42845, 2017.
3.Maekawa M, Tanigawa K, Sakaue T, Hiyoshi H, Kubota E, Joh T, Watanabe Y, Taguchi T, Higashiyama S. Cullin-3 and its adaptor protein ANKFY1 determine the surface level of integrin β1 in endothelial cells. Biol Open. 6, 1707-1719, 2017.
4.Kovačević I, Sakaue T, Majoleé J, Pronk MC, Maekawa M, Geerts D, Fernandez-Borja M, Higashiyama S, Hordijk PL. The Cullin-3-Rbx1-KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB. J Cell Biol. 217, 1015-1032. 2018.