scholarly journals Identification of the growth factor–binding sequence in the extracellular matrix protein MAGP-1

2020 ◽  
Vol 295 (9) ◽  
pp. 2687-2697 ◽  
Author(s):  
Thomas J. Broekelmann ◽  
Nicholas K. Bodmer ◽  
Robert P. Mecham
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Cultured Cells ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Extracellular Matrix Protein ◽  
Surface Plasmon Resonance Analysis ◽  
Factor Binding

Microfibril-associated glycoprotein-1 (MAGP-1) is a component of vertebrate extracellular matrix (ECM) microfibrils that, together with the fibrillins, contributes to microfibril function. Many of the phenotypes associated with MAGP-1 gene inactivation are consistent with dysregulation of the transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) signaling system. We have previously shown that full-length MAGP-1 binds active TGFβ-1 and some BMPs. The work presented here further defines the growth factor–binding domain of MAGP-1. Using recombinant domains and synthetic peptides, along with surface plasmon resonance analysis to measure the kinetics of the MAGP-1–TGFβ-1 interaction, we localized the TGFβ- and BMP-binding site in MAGP-1 to a 19-amino acid–long, highly acidic sequence near the N terminus. This domain was specific for binding active, but not latent, TGFβ-1. Growth factor activity experiments revealed that TGFβ-1 retains signaling activity when complexed with MAGP-1. Furthermore, when bound to fibrillin, MAGP-1 retained the ability to interact with TGFβ-1, and active TGFβ-1 did not bind fibrillin in the absence of MAGP-1. The absence of MAGP was sufficient to raise the amount of total TGFβ stored in the ECM of cultured cells, suggesting that the MAGPs compete with the TGFβ large latent complex for binding to microfibrils. Together, these results indicate that MAGP-1 plays an active role in TGFβ signaling in the ECM.

scholarly journals Fibromodulin Modulates Chicken Skeletal Muscle Development via the Transforming Growth Factor-β Signaling Pathway

Animals ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1477
Author(s):  
Huadong Yin ◽  
Can Cui ◽  
Shunshun Han ◽  
Yuqi Chen ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Matrix Protein ◽  
Muscle Development ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Skeletal Muscle Development

Fibromodulin (Fmod), which is an extracellular matrix protein, belongs to the extracellular matrix small-leucine-rich proteoglycan family. Fmod is abundantly expressed in muscles and connective tissues and is involved in biological regulation processes, including cell apoptosis, cell adhesion, and modulation of cytokine activity. Fmod is the main regulator of myostatin, which controls the development of muscle cells, but its regulatory path is unknown. Chicken models are ideal for studying embryonic skeletal muscle development; therefore, to investigate the mechanism of Fmod in muscle development, Fmod-silenced and Fmod-overexpressed chicken myoblasts were constructed. The results showed that Fmod plays a positive role in differentiation by detecting the expression of myogenic differentiation markers, immunofluorescence of MyHC protein, and myotube formation in myoblasts. Fmod regulates expression of atrophy-related genes to alleviate muscle atrophy, which was confirmed by histological analysis of breast muscles in Fmod-modulated chicks in vivo. Additionally, genes differentially expressed between Fmod knockdown and normal myoblasts were enriched in the signaling pathway of transforming growth factor β (TGF-β). Both Fmod-silenced and Fmod-overexpressed myoblasts regulated the expression of TGFBR1 and p-Smad3. Thus, Fmod can promote differentiation but not proliferation of myoblasts by regulating the TGF-β signaling pathway, which may serve a function in muscular atrophy.

Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency

2007 ◽  
Vol 292 (2) ◽  
pp. F789-F795 ◽  
Author(s):  
Margo P. Cohen ◽  
Gregory T. Lautenslager ◽  
Elizabeth Hud ◽  
Elizabeth Shea ◽  
Amy Wang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Renal Insufficiency ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Glycated Albumin ◽  
Extracellular Matrix Protein ◽  
Type Iv ◽  
Endothelial Growth Factor ◽  
Tgf Β1

Glomerular cells in culture respond to albumin containing Amadori glucose adducts (the principal serum glycated protein), with activation of protein kinase C-β1, increased expression of transforming growth factor (TGF)-β1, the TGF-β type II signaling receptor, and the extracellular matrix proteins α1(IV) collagen and fibronectin and with decreased production of the podocyte protein nephrin. Decreasing the burden of glycated albumin in diabetic db/db mice significantly reduces glomerular overexpression of TGF-β1 mRNA, restores glomerular nephrin immunofluorescence, and lessens proteinuria, mesangial expansion, renal extracellular matrix protein production, and increased glomerular vascular endothelial growth factor (VEGF) immunostaining. In the present study, db/db mice were treated with a small molecule, designated 23CPPA, that inhibits the nonenzymatic condensation of glucose with the albumin protein to evaluate whether increased glycated albumin influences the production of VEGF receptors (VEGFRs) and type IV collagen subchains and ameliorates the development of renal insufficiency. Renal levels of VEGF and VEGFR-1 proteins and serum creatinine concentrations were significantly higher and renal levels of α3(IV) collagen and nephrin proteins and endogenous creatinine clearance values were significantly lower in control diabetic than in age-matched nondiabetic ( db/m) mice. These changes were significantly attenuated in db/db littermate mice treated from 9 to 18 wk of age with 23CPPA. The findings indicate that inhibiting excess nonenzymatic glycation of serum albumin improves renal molecular biology abnormalities and protects against the development of renal insufficiency in the db/db mouse.

Transforming growth factor-β–induced protein (TGFBIp/β ig-h3) activates platelets and promotes thrombogenesis

Blood ◽  
2009 ◽  
Vol 114 (25) ◽  
pp. 5206-5215 ◽  
Author(s):  
Ha-Jeong Kim ◽  
Pan-Kyung Kim ◽  
Sang Mun Bae ◽  
Hye-Nam Son ◽  
Debraj Singh Thoudam ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Growth Factor ◽  
Platelet Activation ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Thrombus Formation ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Type I

Abstract Transforming growth factor-β–induced protein (TGFBIp)/βig-h3 is a 68-kDa extracellular matrix protein that is functionally associated with the adhesion, migration, proliferation, and differentiation of various cells. The presence of TGFBIp in platelets led us to study the role of this protein in the regulation of platelet functions. Upon activation, platelet TGFBIp was released and associated with the platelets. TGFBIp mediates not only the adhesion and spread of platelets but also activates them, resulting in phosphatidylserine exposure, α-granule secretion, and increased integrin affinity. The fasciclin 1 domains of TGFBIp are mainly responsible for the activation of platelets. TGFBIp promotes thrombus formation on type I fibrillar collagen under flow conditions in vitro and induces pulmonary embolism in mice. Moreover, transgenic mice, which have approximately a 1.7-fold greater blood TGFBIp concentration, are significantly more susceptible to collagen- and epinephrine-induced pulmonary embolism than wild-type mice. These results suggest that TGFBIp, a human platelet protein, plays important roles in platelet activation and thrombus formation. Our findings will increase our understanding of the novel mechanism of platelet activation, contributing to a better understanding of thrombotic pathways and the development of new antithrombotic therapies.

Abstract 11021: Circulating Cardiac Transforming Growth Factor-β is a Principal Determinant in Inducing Myocardial Hypertrophy in Transgenic Mice Overexpressing Exogenous Hepatic Transforming Growth Factor-β

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Shaukat A Khan ◽  
Takeshi Tsuda
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Myocardial Hypertrophy ◽  
Cardiac Fibroblasts ◽  
Mrna Level ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Potent Growth

Introduction: Transforming growth factor (TGF)-β is a potent growth factor that induces myocardial hypertrophy, but an interaction between circulating and myocardial TGF-β has been poorly understood. An extracellular matrix protein, fibulin-2, mediates exogenous TGF-β-induced endogenous TGF-β up-regulation in isolated cardiac fibroblasts. Hypothesis: Systemic TGF-β-induced myocardial hypertrophy is mediated primarily by enhanced myocardial TGF-β via paracrine fashion. Methods: We created double mutant mice with TGF-β1 over-expressing transgenic mice (TG) and fibulin-2 knockout mice (KO). TG developed myocardial hypertrophy due to excessive circulating hepatic TGF-β. We studied TGF-β dynamics between tissues and circulation during hypertrophic changes. Results: TG/WT developed significant myocardial hypertrophy at 8 weeks compared with non-TG (NTG) groups. Hypertrophy in TG/KO was significantly attenuated compared with TG/WT. Myocardial TGF-β mRNA level was significantly up-regulated in TG/WT compared with TG/KO or NGT groups, so was Smad2 activation, but myocardial TGF-β bioactivity was no different among all four groups. Serum carrier-bound TGF-β was significantly higher in TG/WT than in TG/KO or NTG groups, but free unbound TGF-β level was equally elevated in TG groups compared with NTG groups. Thus, hypertrophy in TG/WT may be attributed to increased serum carrier-bound TGF-β levels, not to either myocardial TGF-β activity or serum unbound TGF-β levels. Endogenous TGF-β mRNA level in kidney and liver was equally increased in TG group compared with NTG group, and was comparable in all 4 groups in lung, suggesting fibulin-2 was not involved in TGF-β-induced TGF-β synthesis in kidney, liver, or lung. Conclusions: Hepatic TGF-β-induced-myocardial TGF-β up-regulation was mediated by fibulin-2. In TG/WT, up-regulated myocardial TGF-β was mainly secreted into circulation as a soluble carrier-bound form and did not directly induce hypertrophy via paracrine fashion. It is this circulating endogenous myocardial TGF-β rather than transgene-induced hepatic TGF-β that is responsible for myocardial hypertrophy in TG/WT. Heart is a major endocrine organ in secreting circulating endogenous TGF-β in inducing myocardial hypertrophy.

scholarly journals Role of LTBP4 in alveolarization, angiogenesis, and fibrosis in lungs

2017 ◽  
Vol 313 (4) ◽  
pp. L687-L698 ◽  
Author(s):  
Insa Bultmann-Mellin ◽  
Katharina Dinger ◽  
Carolin Debuschewitz ◽  
Katharina M. A. Loewe ◽  
Yvonne Melcher ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Elastic Fiber ◽  
Transforming Growth Factor Β ◽  
Matrix Proteins ◽  
Extracellular Matrix Protein ◽  
Elastic Fibers ◽  
Fiber Network

Deficiency of the extracellular matrix protein latent transforming growth factor-β (TGF-β)-binding protein-4 (LTBP4) results in lack of intact elastic fibers, which leads to disturbed pulmonary development and lack of normal alveolarization in humans and mice. Formation of alveoli and alveolar septation in pulmonary development requires the concerted interaction of extracellular matrix proteins, growth factors such as TGF-β, fibroblasts, and myofibroblasts to promote elastogenesis as well as vascular formation in the alveolar septae. To investigate the role of LTBP4 in this context, lungs of LTBP4-deficient ( Ltbp4−/−) mice were analyzed in close detail. We elucidate the role of LTBP4 in pulmonary alveolarization and show that three different, interacting mechanisms might contribute to alveolar septation defects in Ltbp4−/− lungs: 1) absence of an intact elastic fiber network, 2) reduced angiogenesis, and 3) upregulation of TGF-β activity resulting in profibrotic processes in the lung.

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