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.

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

scholarly journals Utilizing the ABC Transporter for Growth Factor Production by fleQ Deletion Mutant of Pseudomonas fluorescens

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 679
Author(s):  
Benedict-Uy Fabia ◽  
Joshua Bingwa ◽  
Jiyeon Park ◽  
Nguyen-Mihn Hieu ◽  
Jung-Hoon Ahn
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Pseudomonas Fluorescens ◽  
Abc Transporter ◽  
Transforming Growth Factor Beta ◽  
Deletion Mutant ◽  
Transforming Growth Factor ◽  
Gene Knockout ◽  
Type I ◽  
Double Deletion

Pseudomonas fluorescens, a gram-negative bacterium, has been proven to be a capable protein manufacturing factory (PMF). Utilizing its ATP-binding cassette (ABC) transporter, a type I secretion system, P. fluorescens has successfully produced recombinant proteins. However, besides the target proteins, P. fluorescens also secretes unnecessary background proteins that complicate protein purification and other downstream processes. One of the background proteins produced in large amounts is FliC, a flagellin protein. In this study, the master regulator of flagella gene expression, fleQ, was deleted from P. fluorescens Δtp, a lipase and protease double-deletion mutant, via targeted gene knockout. FleQ directs flagella synthesis, so the new strain, P. fluorescens ΔfleQ, does not produce flagella-related proteins. This not only simplifies purification but also makes P. fluorescens ΔfleQ an eco-friendly expression host because it will not survive outside a controlled environment. Six recombinant growth factors, namely, insulin-like growth factors I and II, beta-nerve growth factor, fibroblast growth factor 1, transforming growth factor beta, and tumor necrosis factor beta, prepared using our supercharging method, were successfully secreted by P. fluorescens ΔfleQ. Our findings demonstrate the potential of P. fluorescens ΔfleQ, combined with our supercharging process, as a PMF.

scholarly journals Formation of hetero-oligomeric complexes of type I and type II receptors for transforming growth factor-beta.

1994 ◽  
Vol 269 (31) ◽  
pp. 20172-20178 ◽  
Author(s):  
H. Yamashita ◽  
P. ten Dijke ◽  
P. Franzén ◽  
K. Miyazono ◽  
C.H. Heldin
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Type I ◽  
Type Ii ◽  
Growth Factor Beta

Collagen matrices attenuate the collagen-synthetic response of cultured fibroblasts to TGF-beta

1995 ◽  
Vol 108 (3) ◽  
pp. 1251-1261 ◽  
Author(s):  
R.A. Clark ◽  
L.D. Nielsen ◽  
M.P. Welch ◽  
J.M. McPherson
Keyword(s):  
Growth Factor ◽  
Granulation Tissue ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Collagen Matrix ◽  
Dermal Fibroblasts ◽  
Type I ◽  
Collagen Gels ◽  
Type I Procollagen ◽  
Growth Factor Beta

Transforming growth factor-beta, a potent modulator of cell function, induces fibroblasts cultured on plastic to increase collagen synthesis. In 5- and 7-day porcine skin wounds, which have minimal to moderate collagen matrix, respectively, transforming growth factor-beta and type I procollagen were coordinately expressed throughout the granulation tissue. However, in 10-day collagen-rich granulation tissue type I procollagen expression diminished despite persistence of transforming growth factor-beta. To investigate whether collagen matrix attenuates the collagen-synthetic response of fibroblasts to transforming growth factor-beta, we cultured human dermal fibroblasts in conditions that simulate collagen-rich granulation tissue. Therefore, human dermal fibroblasts were suspended in attached collagen gels and collagen and noncollagen production was assayed in the absence and presence of transforming growth factor-beta. Although transforming growth factor-beta stimulated collagen synthesis by fibroblasts cultured in the collagen gels, these fibroblasts consistently produced less collagen than similarly treated fibroblasts cultured on plastic. This phenomenon was not secondary to nonspecific binding of transforming growth factor-beta to the collagen matrix. Fibroblasts cultured in a fibrin gel responded to transforming growth factor-beta similarly to fibroblasts cultured on plastic. Using immunofluorescence probes to type I procollagen, we observed that transforming growth factor-beta increased type I procollagen expression in most fibroblasts cultured on plastic, but only in occasional fibroblasts cultured in collagen gels. From these data we conclude that collagen matrices attenuate the collagen synthetic response of fibroblast to transforming growth factor-beta in vitro and possibly in vivo.

Cloning of a growth arrest-specific and transforming growth factor beta-regulated gene, TI 1, from an epithelial cell line

1991 ◽  
Vol 11 (10) ◽  
pp. 5338-5345
Author(s):  
B Kallin ◽  
R de Martin ◽  
T Etzold ◽  
V Sorrentino ◽  
L Philipson
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Lung Epithelial Cells ◽  
Epithelial Cell Line ◽  
Type I ◽  
Tgf Beta ◽  
Protein Synthesis Inhibitors ◽  
Plasminogen Activator Inhibitor 1 ◽  
Growth Factor Beta

By cDNA cloning and differential screening, five genes that are regulated by transforming growth factor beta (TGF beta) in mink lung epithelial cells were identified. A novel membrane protein gene, TI 1, was identified which was downregulated by TGF beta and serum in quiescent cells. In actively growing cells, the TI 1 gene is rapidly and transiently induced by TGF beta, and it is overexpressed in the presence of protein synthesis inhibitors. It appears to be related to a family of transmembrane glycoproteins that are expressed on lymphocytes and tumor cells. The four other genes were all induced by TGF beta and correspond to the genes of collagen alpha type I, fibronectin, plasminogen activator inhibitor 1, and the monocyte chemotactic cell-activating factor (JE gene) previously shown to be TGF beta regulated.

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