CUL3 network system in angiogenesis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H04698
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Ehime University
• Principal Investigator: HIGASHIYAMA SHIGEKI 愛媛大学, プロテオサイエンスセンター, 教授 (60202272)
• Research Collaborator: Sakaue Tomohisa ; Maekawa Masashi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 血管新生 / ユビキチンリガーゼ / cullin3 / BTBドメインタンパク質 / SPOP / ANKFY1 / KCTD10 / VEGFR2

Outline of Final Research Achievements

New blood vessel formation, termed angiogenesis, is an essential process in normal physiology, including tissue development and wound healing, as well as in many pathological conditions such as cancer and diabetes, among other. Endothelial cells play a central role in angiogenesis which is homeostatically regulated on the balance between angiogenic and angiostatic force. We found that CUL3-based ubiquitin E3 ligases play a crucial role of not only sensing this balance, but also regulating multiple steps of angiogenesis, such as endothelial cell growth, spreading and network formation. In this study, we revealed that CUL3-SPOP-DAXX axis positively regulated VEGFR2 mRNA expression, CUL3-ANKFY1-substrate (unidentified yet) axis positively did intracellular membrane trafficking of beta1-Integrin to cell surface, and CUL3-KCTD10-RhoB axis did cell spreading and network formation through the actin dynamics, suggesting that these would be potent targets of anti-angiogenic therapy.

Free Research Field

血管生物学、分子腫瘍学、生化学

Academic Significance and Societal Importance of the Research Achievements

血管内皮細胞の増殖促進と抑制のシグナルバランス分子機構をタンパク質代謝回転の側面から深く解明することは、これまでの血管内皮細胞増殖シグナル経路以外の血管新生の新たな分子制御機構を解明できる。このことは、これまでのVEGF-VEGFRシステムを中心とした血管内皮細胞増殖シグナル伝達経路とは全く異なる新たな標的分子創薬の側面を作る事が期待でき、今までに無い治療戦略を提案することで社会貢献が可能となり、その意義は極めて大きい。