scholarly journals LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Carl Herdenberg ◽  
Pascal M. Mutie ◽  
Ola Billing ◽  
Ahmad Abdullah ◽  
Rona J. Strawbridge ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Lipid Metabolism ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Bmp Signaling ◽  
Null Mouse ◽  
Growth Factor Signaling

AbstractLeucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Here, we show that Lrig-null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis and bone morphogenetic protein (BMP) signaling. In contrast, transforming growth factor-beta (TGF-β) and receptor tyrosine kinase (RTK) signaling appeared unaltered in Lrig-null cells. The BMP signaling defect was rescued by ectopic expression of LRIG1 or LRIG3 but not by expression of LRIG2. Caenorhabditis elegans with mutant LRIG/sma-10 variants also exhibited a lipid storage defect. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease.

scholarly journals Serum transforming growth factor-beta 1 levels in normoalbuminuric and normotensive patients with type 2 diabetes. Effect of metformin and rosiglitazone

HORMONES ◽  
2008 ◽  
Vol 7 (1) ◽  
pp. 70-76 ◽  
Author(s):  
Serkan Yener ◽  
Abdurrahman Comlekci ◽  
Baris Akinci ◽  
Pinar Akan ◽  
Tevfik Demir ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Factor Beta

scholarly journals It Takes Two to Tango: Endothelial TGFβ/BMP Signaling Crosstalk with Mechanobiology

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1965 ◽  
Author(s):  
Christian Hiepen ◽  
Paul-Lennard Mendez ◽  
Petra Knaus
Keyword(s):  
Shear Stress ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Research Field ◽  
Bmp Signaling ◽  
Growth Factor Signaling ◽  
Mechanical Stimuli ◽  
Signaling Crosstalk

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGFβ) superfamily of cytokines. While some ligand members are potent inducers of angiogenesis, others promote vascular homeostasis. However, the precise understanding of the molecular mechanisms underlying these functions is still a growing research field. In bone, the tissue in which BMPs were first discovered, crosstalk of TGFβ/BMP signaling with mechanobiology is well understood. Likewise, the endothelium represents a tissue that is constantly exposed to multiple mechanical triggers, such as wall shear stress, elicited by blood flow or strain, and tension from the surrounding cells and to the extracellular matrix. To integrate mechanical stimuli, the cytoskeleton plays a pivotal role in the transduction of these forces in endothelial cells. Importantly, mechanical forces integrate on several levels of the TGFβ/BMP pathway, such as receptors and SMADs, but also global cell-architecture and nuclear chromatin re-organization. Here, we summarize the current literature on crosstalk mechanisms between biochemical cues elicited by TGFβ/BMP growth factors and mechanical cues, as shear stress or matrix stiffness that collectively orchestrate endothelial function. We focus on the different subcellular compartments in which the forces are sensed and integrated into the TGFβ/BMP growth factor signaling.

dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen, Dpp

Development ◽  
1997 ◽  
Vol 124 (20) ◽  
pp. 4113-4120 ◽  
Author(s):  
S.M. Jackson ◽  
H. Nakato ◽  
M. Sugiura ◽  
A. Jannuzi ◽  
R. Oakes ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Cellular Responses ◽  
Growth Factor Signaling ◽  
Tgf Beta ◽  
Morphogenetic Protein

Decapentaplegic (Dpp) is a Drosophila member of the Transforming Growth Factor-beta (TGF-beta)/Bone Morphogenetic Protein (BMP) superfamily of growth factors. Dpp serves as a classical morphogen, where concentration gradients of this secreted factor control patterning over many cell dimensions. Regulating the level of Dpp signaling is therefore critical to its function during development. One type of molecule proposed to modulate growth factor signaling at the cell surface are integral membrane proteoglycans. We show here that division abnormally delayed (dally), a Drosophila member of the glypican family of integral membrane proteoglycans is required for normal Dpp signaling during development, affecting cellular responses to this morphogen. Ectopic expression of dally+ can alter the patterning activity of Dpp, suggesting a role for dally+ in modulating Dpp signaling strength. These findings support a role for members of the glypican family in controlling TGF-beta/BMP activity in vivo by affecting signaling at the cell surface.

Thrombospondin-1 (TSP1), Transforming Growth Factor-Beta (TGFb) and Connective Tissue Growth Factor (CTGF) are Involved in the Pathophysiology of Diabetic Retinopathy,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3275-3275
Author(s):  
Raul A. De La Cadena ◽  
Mario C Rico ◽  
Fabiola Del Carpio-Cano ◽  
Fayez Safadi ◽  
Satya P. Kunapuli ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Growth Factor ◽  
Western Blotting ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Control Groups ◽  
Vitreous Fluid ◽  
Growth Factor Beta

Abstract Abstract 3275 Background: Diabetic retinopathy (DR) is a progressive disease that affects over 4 million people in the United States and is one of the leading causes of blindness. The pathophysiology of the early events (no evidence of DR) leading to diabetic retinopathy is still not fully understood. Recent studies have proposed that levels of TSP1 (Arch Ophthalmol 127:507, 2009) and CTGF (Diabetes Care 27:758, 2004) may play a role in shifting the angiogenic balance and pathogenesis of DR. We postulate that during acute and chronic inflammation, as seen in type-2 diabetes a pro-inflammatory axis comprised by TSP1, transforming growth factor-beta (TGF-b) and CTGF may play a significant role in the progression of NPDR to PDR. Methods: This is a prospective control study comprised to date of: a) six (6) human subjects with NPDR, b) eleven (11) subjects with PDR, c) five (5) subjects without type-2 diabetes but in need of pars plana vitrectomy, and d) seventeen (17) normal human volunteers. Plasma samples were obtained from all groups (a-d) after signing an informed consent approved by our institution's IRB committee. Vitreous fluid (VF) was collected from subjects in b and c. Cytokine profile was determined by Multiplex Assay. TSP1, TGF-b and CTGF were assessed by commercially available ELISA assays and visualized by Western-blotting technique. Results: TNFa in conjunction with other pro-inflammatory cytokines was found elevated in NPDR subjects when compared to subjects in control groups (c-d, P<0.05). The evidence of acute inflammation in the NPDR group was not only evident by higher levels of TNFa but also TSP1 and TGF-b when compared to control groups (P<0.002 and P<0.001 respectively). Interestingly, the TSP1 profile seen in the NPDR subjects changed significantly (lower levels) when compared to PDR subjects (P<0.002) and was even significantly different from that one seen in control subjects. This early foot print observed for TSP1 was similar to the IL-4 profile (P<0.003 NPDR vs PDR, P<0.0002 NPDR vs controls) a molecule considered to be anti-angiogenic like TSP1. CTGF plasma levels were increased in PDR subjects in plasma (mean 1.67 + 0.27 SEM pg/ml) when compared to NPDR subjects (0.77 + 0.22 pg/ml, P<0.05) and the levels were also higher in VH of PDR subjects when compared with VH controls subjects. On Western-blotting analysis, CTGF and TSP1 in plasma and in VH showed evidence of proteolytic fragmentation, a phenomenon that has been associated with potential promotion of angiogenesis and fibrosis. Summary: Our findings are in agreement with the proposed hypothesis that TSP1 in systemic circulation or in the micro environment (vitreous fluid) in conjunction with TGF-b represent a pro-inflammatory axis in the disease progression from NPDR to PDR with CTGF as the effector molecule placing this axis as a potential therapeutic intervention to prevent progression of disease and to improve quality of life in patients afflicted by NPDR. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Changes of transforming growth factor beta 1 in patients with type 2 diabetes and diabetic nephropathy

Medicine ◽  
2017 ◽  
Vol 96 (15) ◽  
pp. e6583 ◽  
Author(s):  
Yong-Chao Qiao ◽  
Yin-Ling Chen ◽  
Yan-Hong Pan ◽  
Wei Ling ◽  
Fang Tian ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Factor Beta

scholarly journals Targets and Candidate Agents for Type 2 Diabetes Treatment with Computational Bioinformatics Approach

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Qiong Wang ◽  
Zhigang Zhao ◽  
Jing Shang ◽  
Wei Xia
Keyword(s):  
Type 2 Diabetes ◽  
Growth Factor ◽  
Small Molecules ◽  
Transforming Growth Factor Beta ◽  
Drug Targets ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Type 2 Diabetes Treatment ◽  
Systematic Understanding

We sought to explore the molecular mechanism of type 2 diabetes (T2D) and identify potential drug targets and candidate agents for T2D treatment. The differentially expressed genes (DEGs) were assessed between human pancreatic islets with T2D and normal islets. The dysfunctional pathways, the potential transcription factor, and microRNA targets were analyzed by bioinformatics methods. Moreover, a group of bioactive small molecules were identified based on the connectivity map database. The pathways of Eicosanoid Synthesis, TGF-beta signaling pathway, Prostaglandin Synthesis and Regulation, and Integrated Pancreatic Cancer Pathway were found to be significantly dysregulated in the progression of T2D. The genes ofZADH2(zinc binding alcohol dehydrogenase domain containing 2),BTBD3(BTB (POZ) domain containing 3), Cul3-based ligases,  LTBP1(latent-transforming growth factor beta binding protein 1),PDGFRA(alpha-type platelet-derived growth factor receptor), andFST(follistatin) were determined to be significant nodes regulated by potential transcription factors and microRNAs. Besides, two small molecules (sanguinarine and DL-thiorphan) were identified to be capable of reverse T2D. In the present study, a systematic understanding for the mechanism underlying T2D development was provided with biological informatics methods. The significant nodes and bioactive small molecules may be drug targets and candidate agents for T2D treatment.

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