Glycoprotein M6B Interacts with TβRI to Activate TGF-β-Smad2/3 Signaling and Promote Smooth Muscle Cell Differentiation

Author:

Zhang Xiaomeng1ORCID,Xie Huaning1,Chang Pan2,Zhao Huishou1,Xia Yunlong1,Zhang Ling1,Guo Xiong3,Huang Chong1,Yan Feng1,Hu Lang1,Lin Chen1,Li Yueyang1,Xiong Zhenyu4,Wang Xiong1,Li Guohua1,Deng Longxiang1,Wang Shan1,Tao Ling1

Affiliation:

1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China

2. Central Laboratory, Second Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi, People's Republic of China

3. Department of Cardiology, Hospital of People's Liberation Army, Golmud, Qinghai, People's Republic of China

4. Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China

Abstract

Abstract Smooth muscle cells (SMCs), which form the walls of blood vessels, play an important role in vascular development and the pathogenic process of vascular remodeling. However, the molecular mechanisms governing SMC differentiation remain poorly understood. Glycoprotein M6B (GPM6B) is a four-transmembrane protein that belongs to the proteolipid protein family and is widely expressed in neurons, oligodendrocytes, and astrocytes. Previous studies have revealed that GPM6B plays a role in neuronal differentiation, myelination, and osteoblast differentiation. In the present study, we found that the GPM6B gene and protein expression levels were significantly upregulated during transforming growth factor-β1 (TGF-β1)-induced SMC differentiation. The knockdown of GPM6B resulted in the downregulation of SMC-specific marker expression and repressed the activation of Smad2/3 signaling. Moreover, GPM6B regulates SMC Differentiation by Controlling TGF-β-Smad2/3 Signaling. Furthermore, we demonstrated that similar to p-Smad2/3, GPM6B was profoundly expressed and coexpressed with SMC differentiation markers in embryonic SMCs. Moreover, GPM6B can regulate the tightness between TβRI, TβRII, or Smad2/3 by directly binding to TβRI to activate Smad2/3 signaling during SMC differentiation, and activation of TGF-β-Smad2/3 signaling also facilitate the expression of GPM6B. Taken together, these findings demonstrate that GPM6B plays a crucial role in SMC differentiation and regulates SMC differentiation through the activation of TGF-β-Smad2/3 signaling via direct interactions with TβRI. This finding indicates that GPM6B is a potential target for deriving SMCs from stem cells in cardiovascular regenerative medicine. Stem Cells  2018 Stem Cells  2019;37:190–201

Funder

National Science Funds of China

Program for Changjiang Scholars and Innovative Research Teams in the University

Fourth Military Medical University‘s Young Talent Project

National Science Fund for Distinguished Young Scholars of China

National Key Basic Research Program of China

Key Science and Technology Innovation Team in the Shaanxi Province

Major Science and Technology Project of China “Significant New Drug Development”

Key Problems of Social Development Science and Technology of the Shaanxi Province

Shaanxi Key Laboratory of Ischemic Cardiovascular Disease

National Science Foundation of China

Fourth Military Medical University

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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