Homeobox D3, A Novel Link Between Bone Morphogenetic Protein 9 and Transforming Growth Factor Beta 1 Signaling

JOURNAL OF MOLECULAR BIOLOGY

卷:432

Article

Wang, Lumin^1,2  Yao, Jiayi²  Yu, Tongtong^2,3  Zhang, Daoqin²  Qiao, Xiaojing²  Yao, Zehao^2,4  Wu, Xiuju²  Zhang, Li²  Bostrom, Kristina, I^2,5  Yao, Yucheng² 

[1] Xian Jiaotong Univ Hlth Sci Ctr, Sch Basic Med Sci, Dept Cell Biol & Genet, Xian, Peoples R China

[2] UCLA, Div Cardiol, David Geffen Sch Med, Box 951679, Los Angeles, CA 90095 USA

[3] China Med Univ, Dept Cardiol, Shengjing Hosp, Shenyang, Peoples R China

[4] Nankai Univ, Coll Life Sci, Tianjin, Peoples R China

[5] UCLA, Mol Biol Inst, Los Angeles, CA 90095 USA

关键词: endothelium;    bone morphogenetic protein;    Notch;    activin receptor-like kinase 1;    vascular development;   

DOI  :  10.1016/j.jmb.2020.01.043

来源: Elsevier

【 摘 要 】

Aims Several signaling pathways contribute to endothelial-mesenchymal transitions and vascular calcification, including bone morphogenetic protein (BMP) and transforming growth factor (TGF) beta signaling. The transcription factor homeobox D3 (Hoxd3) is known to regulate an invasive endothelial phenotype, and the aim of the study is to determine if HOXD3 modulates BMP and TGF beta signaling in the endothelium. Methods and Research We report that the endothelium with high BMP activity due to the loss of BMP inhibitor matrix Gla protein (MGP) shows induction of Hoxd3. HOXD3 is part of a BMP-triggered cascade. When activated by BMP9, activin receptor-like kinase (ALK) 1 induces HOXD3 expression. Hoxd3 promoter is a direct target of phosphorylated (p) SMAD1 , a mediator of BMP signaling. High BMP activity further results in enhanced TGF beta signaling due to induction of TGF beta 1 and its receptor, ALK5. This is mediated by HOXD3, which directly targets the Tgfb1 promoter. Finally, TGF beta 1 and BMP9 stimulate the expression of MGP, which limits the enhanced ALK1 induction by counteracting BMP4. The cascade of BMP9-HOXD3-TGF beta also affects Notch signaling and angiogenesis through induction of Notch ligand Jagged 2 and suppression of Notch ligand delta-like 4 (DII4). Conclusion The results suggest that HOXD3 is a novel link between BMP9/ALK1 and TGF beta 1/ALK5 signaling. Translational perspective BMP and TGF beta signaling are instrumental in vascular disease such as vascular calcification and atherosclerosis. This study demonstrated a novel type of cross talk between endothelial BMP and TGF beta signaling as mediated by HOXD3. The results provide a possible therapeutic approach to control dysfunctional BMP and TGF beta signaling by regulating HOXD3. (C) 2020 Elsevier Ltd. All rights reserved.

【 授权许可】

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