scholarly journals A Highly Selective Chemical Probe for Activin Receptor-like Kinases ALK4 and ALK5

2020 ◽  
Author(s):  
Thomas Hanke ◽  
Jong Fu Wong ◽  
Benedict-Tilmann Berger ◽  
Ismahan Abdi ◽  
Lena Marie Berger ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Heart Diseases ◽  
Negative Control ◽  
Cellular Systems ◽  
Receptor Protein ◽  
Chemical Probe ◽  
Activin Receptor ◽  
Control Compound

AbstractThe transforming growth factor beta-receptor I/activin receptor-like kinase 5 (TGFBR1/ALK5) and its close homologue ALK4 are receptor protein kinases associated with the development of diverse diseases, including cancer, fibrosis, heart diseases and dysfunctional immune response. Therefore, ALK4/5 are among the most studied kinases and several inhibitors have been developed. However, current commercially available inhibitors either lack selectivity or have not been comprehensively characterized, limiting their value for studying ALK4/5 function in cellular systems. To this end, we report the characterization of the 2-oxo-imidazopyridine, TP-008, a potent chemical probe with dual activity for ALK4 and ALK5 as well as the development of a matching negative control compound. TP-008 has excellent cellular potency and strongly abrogates phosphorylation of the substrate SMAD2 (mothers against decapentaplegic homolog 2). Thus, this chemical probe offers an excellent tool for mechanistic studies on the ALK4/5 signaling pathway and the contribution of these targets to disease.

scholarly journals Captopril reverses high-glucose-induced growth effects on LLC-PK1 cells partly by decreasing transforming growth factor-beta receptor protein expressions.

1996 ◽  
Vol 7 (8) ◽  
pp. 1207-1215 ◽  
Author(s):  
J Y Guh ◽  
M L Yang ◽  
Y L Yang ◽  
C C Chang ◽  
L Y Chuang
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Receptor Protein ◽  
Tgf Beta ◽  
Beta Receptor ◽  
Protein Expressions ◽  
Beta Receptors ◽  
Growth Factor Beta

Transforming growth factor beta (TGF-beta) may be important in the pathogenesis of diabetic nephropathy, and captopril is effective in treating this disorder. However, the mechanisms of this therapeutic effect as related to TGF-beta and its receptors are not known. Thus, the effects of captopril on cellular growth, TGF-beta 1, and TGF-beta receptors were studied in LLC-PK1 cells cultured in normal (11 mM) or high glucose (27.5 mM). This study found that glucose dose-dependently inhibited cellular mitogenesis while inducing hypertrophy in these cells at 72 h of culture, concomitantly with enhanced TGF-beta 1 messenger RNA (mRNA) and TGF-beta receptor Types I and II protein expressions. Captopril dose-dependently (0.1 to 10 mM) increased cellular mitogenesis and inhibited hypertrophy in these cells. Moreover, captopril also decreased TGF-beta receptor Types I and II protein expressions dose-dependently. However, TGF-beta 1 mRNA was not affected by captopril. It was concluded that high glucose decreased cellular mitogenesis while increasing hypertrophy concomitantly with increased TGF-beta 1 mRNA and TGF-beta receptors in LLC-PK1 cells. Captopril can reverse high-glucose-induced growth effects by decreasing TGF-beta receptor protein expressions.

scholarly journals Characterization of distinct functional domains of transforming growth factor beta.

1993 ◽  
Vol 90 (18) ◽  
pp. 8628-8632 ◽  
Author(s):  
J. K. Burmester ◽  
S. W. Qian ◽  
A. B. Roberts ◽  
A. Huang ◽  
S. Amatayakul-Chantler ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Functional Domains ◽  
Growth Factor Beta

scholarly journals Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function

2016 ◽  
Vol 44 (4) ◽  
pp. 1142-1149 ◽  
Author(s):  
Amaya García de Vinuesa ◽  
Matteo Bocci ◽  
Kristian Pietras ◽  
Peter ten Dijke
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
New Combination ◽  
Current Status ◽  
Human Antibody ◽  
Type I ◽  
Activin Receptor ◽  
Alternative Pathways ◽  
Receptor Like Kinase

Angiogenesis is a hallmark of cancer and is now a validated therapeutic target in the clinical setting. Despite the initial success, anti-angiogenic compounds impinging on the vascular endothelial growth factor (VEGF) pathway display limited survival benefits in patients and resistance often develops due to activation of alternative pathways. Thus, finding and validating new targets is highly warranted. Activin receptor-like kinase (ALK)1 is a transforming growth factor beta (TGF-β) type I receptor predominantly expressed in actively proliferating endothelial cells (ECs). ALK1 has been shown to play a pivotal role in regulating angiogenesis by binding to bone morphogenetic protein (BMP)9 and 10. Two main pharmacological inhibitors, an ALK1-Fc fusion protein (Dalantercept/ACE-041) and a fully human antibody against the extracellular domain of ALK1 (PF-03446962) are currently under clinical development. Herein, we briefly recapitulate the role of ALK1 in blood vessel formation and the current status of the preclinical and clinical studies on inhibition of ALK1 signalling as an anti-angiogenic strategy. Future directions in terms of new combination regimens will also be presented.

scholarly journals Characterization of the molecular mechanism involved in the activation of hyaluronan synthetase by platelet-derived growth factor in human mesothelial cells

1992 ◽  
Vol 283 (1) ◽  
pp. 165-170 ◽  
Author(s):  
P Heldin ◽  
T Asplund ◽  
D Ytterberg ◽  
S Thelin ◽  
T C Laurent
Keyword(s):  
Growth Factor ◽  
Molecular Mechanism ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Mesothelial Cells ◽  
Platelet Derived Growth Factor ◽  
Synthetase Activity ◽  
Normal Human ◽  
Stimulation Of

The molecular mechanism involved in the stimulation of hyaluronan synthetase in normal human mesothelial cells was investigated. Exposure of mesothelial cells to platelet-derived growth factor (PDGF)-BB stimulated hyaluronan synthetase activity, measured in isolated membrane preparations, as well as hyaluronan secretion into the medium. The effect on hyaluronan synthetase was maximal after 6 h of treatment. In contrast, the stimulatory effect of transforming growth factor-beta 1 reached a maximum after 24 h. The stimulatory effect of PDGF-BB was inhibited by cycloheximide. The phosphotyrosine phosphatase inhibitor vanadate was found to stimulate hyaluronan synthetase activity, and to potentiate the effect of PDGF-BB. The protein kinase C (PKC) stimulator phorbol 12-myristate 13-acetate (PMA) also stimulated hyaluronan synthetase; furthermore, depletion of PKC by preincubation of the cells with PMA led to an inhibition of the PDGF-BB-induced stimulation of hyaluronan synthetase activity. Thus the PDGF-BB-induced stimulation of hyaluronan synthetase activity is dependent on protein synthesis and involves tyrosine phosphorylation and activation of PKC.

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