SB-431542 Is a Potent and Specific Inhibitor of Transforming Growth Factor-β Superfamily Type I Activin Receptor-Like Kinase (ALK) Receptors ALK4, ALK5, and ALK7

2002 ◽  
Vol 62 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Gareth J. Inman ◽  
Francisco J. Nicolás ◽  
James F. Callahan ◽  
John D. Harling ◽  
Laramie M. Gaster ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Specific Inhibitor ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Activin Receptor ◽  
Receptor Like Kinase

Contribution of activin receptor–like kinase 5 (transforming growth factor β receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts

2006 ◽  
Vol 54 (4) ◽  
pp. 1309-1316 ◽  
Author(s):  
Yunliang Chen ◽  
Xu Shi-Wen ◽  
Mark Eastwood ◽  
Carol M. Black ◽  
Christopher P. Denton ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Receptor Type ◽  
Type I ◽  
Activin Receptor ◽  
Receptor Like Kinase ◽  
Β Receptor

scholarly journals Activin receptor-like kinase-2 inhibits activin signaling by blocking the binding of activin to its type II receptor

2007 ◽  
Vol 195 (1) ◽  
pp. 95-103 ◽  
Author(s):  
Nina Renlund ◽  
Francis H O’Neill ◽  
LiHua Zhang ◽  
Yisrael Sidis ◽  
Jose Teixeira
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Type I ◽  
Type Ii ◽  
Activin Receptor ◽  
Activin Signaling ◽  
Endogenous Expression ◽  
Receptor Like Kinase

Activin receptor-like kinase-2 (Alk2) has been shown to be a promiscuous type I receptor for the transforming growth factor β (TGFβ) family of growth and differentiation factors, such as activin, bone morphogenetic proteins, and Müllerian inhibiting substance (MIS). We have studied the putative role of Alk2 in activin signaling using MA-10 cells, a mouse transformed Leydig cell line, in which endogenous expression of cytochrome P450 c17 hydroxylase/C17–20 lyase mRNA is inhibited by both MIS and activin A. Overexpression of Alk2 in MA-10 cells inhibited the activation of the activin-responsive CAGA-luciferase reporter and, conversely, transfection of siRNA for Alk2 increased the response. In contrast, overexpression of the MIS type II receptor in MA-10 cells increased the activin-mediated induction of CAGA-luciferase approximately fivefold, which we hypothesized occurs by MIS type II receptor sequestering endogenous Alk2. Binding experiments with 125I-labeled activin show that the underlying mechanism of Alk2-mediated inhibition of activin signaling involves Alk2 blocking the access of activin to its type II receptor, which we show can bind Alk2 in the absence of ligand. These results show that the complement of other type I receptors in addition to the ligand-specific type I receptor can provide an important mechanism for modulating cell-specific responses to members of the TGFβ family.

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 Inhibition of transforming growth factor-β via the activin receptor-like kinase-5 inhibitor attenuates pulmonary fibrosis

2015 ◽  
Vol 11 (5) ◽  
pp. 3808-3813 ◽  
Author(s):  
RHUN YIAN KOH ◽  
CHOOI LING LIM ◽  
BRUCE DAVID UHAL ◽  
MAHA ABDULLAH ◽  
SHARMILI VIDYADARAN ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Activin Receptor ◽  
Receptor Like Kinase

scholarly journals Transforming Growth Factor β (TGFβ) Signaling via Differential Activation of Activin Receptor-like Kinases 2 and 5 during Cardiac Development

2002 ◽  
Vol 277 (51) ◽  
pp. 50183-50189 ◽  
Author(s):  
Simone M. Ward ◽  
Jay S. Desgrosellier ◽  
Xiaoli Zhuang ◽  
Joey V. Barnett ◽  
Jonas B. Galper
Keyword(s):  
Promoter Activity ◽  
Transforming Growth Factor ◽  
Cardiac Development ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
In Ovo ◽  
Activin Receptor ◽  
Atrial Cells ◽  
Tgfβ Receptors ◽  
Receptor Like Kinase

Little is known regarding factors that induce parasympathetic responsiveness during cardiac development. We demonstrated previously that in atrial cells cultured from chicks 14 daysin ovo, transforming growth factor β (TGFβ) decreased parasympathetic inhibition of beat rate by the muscarinic agonist, carbamylcholine, by 5-fold and decreased expression of Gαi2. Here in atrial cells 5 daysin ovo,TGFβ increased carbamylcholine inhibition of beat rate 2.5-fold and increased expression of Gαi2. TGFβ also stimulated Gαi2mRNA expression and promoter activity at day 5 while inhibiting them at day 14in ovo. Over the same time course expression of type I TGFβ receptors, chick activin receptor-like kinase 2 and 5 increased with a 2.3-fold higher increase in activin receptor-like kinase 2. Constitutively active activin receptor-like kinase 2 inhibited Gαi2promoter activity, whereas constitutively active activin receptor-like kinase 5 stimulated Gαi2promoter activity independent of embryonic age. In 5-day atrial cells, TGFβ stimulated the p3TP-lux reporter, which is downstream of activin receptor-like kinase 5 and had no effect on the activity of the pVent reporter, which is downstream of activin receptor-like kinase 2. In 14-day cells, TGFβ stimulated both pVent and p3TP-lux. Thus TGFβ exerts opposing effects on parasympathetic response and Gαi2expression by activating different type I TGFβ receptors at distinct stages during cardiac development.

Sign in / Sign up

Export Citation Format

Share Document