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

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

GPM6B Inhibit PCa Proliferation by Blocking Prostate Cancer Cell Serotonin Absorptive Capacity

“…In our experiments, serotonin could promote the proliferation of PCa cell lines, which is consistent with a previous study [ 14 , 15 , 19 ]. On the other side, the overexpression of GPM6B can reverse the effect of serotonin in PCa cell growth.…”

“…Relevant studies have shown that GPM6B can bind to SERT and result in a significant reduction in serotonin uptake [ 14 ]. GPM6B also plays a regulatory role in smooth muscle cell differentiation [ 15 ]. Oncological research on GPM6B has gradually attracted attention in recent years.…”

Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins

“…On the other hand, GlialCAM and MLC1 have been shown to influence intracellular signaling pathways controlling astrocyte activation and proliferation. Several proteins have been identified related to cell signaling within this proteome, such as three different GPCRs (GPR37, GPR37L1 and GPRC5B), a tetraspanin (CD9) ( 41 ) and the four transmembrane domain proteins Glycoprotein M6A and M6B ( 42 , 43 ). Considering the role played by GPCRs, we hypothesize that some of the signaling pathways involving MLC proteins might be caused by the activity of these GPCRs.…”

GDF10 inhibits proliferation and epithelial-mesenchymal transition in triple‐negative breast cancer via upregulation of Smad7

“…GDF10 plays an important role in cell proliferation and differentiation and is also known as BMP-3B due to its close relationship with bone morphogenetic protein-3 (BMP3), another member of the TGF-β superfamily [12]. TGF-β signals through three cell surface receptors, namely TGFBR1/2/3 [13,14]. Stimulation of TGFBR2 activates TGFBR1, which phosphorylates Smad2/3.…”