2. Academic Validation
  3. Proteolytic activation of angiomotin by DDI2 promotes angiogenesis

Proteolytic activation of angiomotin by DDI2 promotes angiogenesis

  • EMBO J. 2023 Jun 23;e112900. doi: 10.15252/embj.2022112900.
Yu Wang # 1,  Yuwen Zhu # 1,  Yebin Wang 1,  Yue Chang 2 3,  Fang Geng 2 3,  Mingyue Ma 1,  Yuan Gu 1,  Aijuan Yu 1,  Rui Zhu 1,  Pengcheng Yu 1,  Zhao Sha 1,  Sixian Qi 1,  Jian Li 1,  Wencao Zhao 1 4,  Weijun Pan 4,  Ruilin Zhang 3,  Fa-Xing Yu 1
Affiliations

Affiliations

  • 1 Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, the State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 2 School of Life Sciences, Fudan University, Shanghai, China.
  • 3 TaiKang Medical School (School of Basic Medical Sciences), Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China.
  • 4 Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), Shanghai, China.
  • # Contributed equally.
PMID: 37350545 DOI: 10.15252/embj.2022112900
Abstract

The scaffolding protein angiomotin (AMOT) is indispensable for vertebrate embryonic angiogenesis. Here, we report that AMOT undergoes cleavage in the presence of lysophosphatidic acid (LPA), a lipid growth factor also involved in angiogenesis. AMOT cleavage is mediated by aspartic Protease DNA damage-inducible 1 homolog 2 (DDI2), and the process is tightly regulated by a signaling axis including neurofibromin 2 (NF2), tankyrase 1/2 (TNKS1/2), and RING finger protein 146 (RNF146), which induce AMOT membrane localization, poly ADP ribosylation, and ubiquitination, respectively. In both zebrafish and mice, the genetic inactivation of AMOT cleavage regulators leads to defective angiogenesis, and the phenotype is rescued by the overexpression of AMOT-CT, a C-terminal AMOT cleavage product. In either physiological or pathological angiogenesis, AMOT-CT is required for vascular expansion, whereas uncleavable AMOT represses this process. Thus, our work uncovers a signaling pathway that regulates angiogenesis by modulating a cleavage-dependent activation of AMOT.

Keywords

AMOT; DDI2; NF2; angiogenesis; protease.

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