ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-β and constitutively active receptor induced gene expression

Lux, Andreas; Salway, Fiona; Dressman, Holly K.; Kröner-Lux, Gabriele; Hafner, Mathias; Day, Philip J.; Marchuk, Douglas A.; Garland, John M.

doi:10.1186/1471-2261-6-13

Cited by 36 publications

(32 citation statements)

References 95 publications

(74 reference statements)

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“…Here, we show that BMP9 elicited potent transcriptional responses in HPAECs, whereas BMP2, BMP4, BMP6, and TGF␤ 1 weakly induced mRNA induction. BMP9 potently induced Id1 and Id2 in HPAECs, consistent with previous studies with BMP9 and caALK1 in endothelial cells (22,25). However, the functional roles of the Id proteins are not entirely clear, as Id1 is reported to be essential for BMP6-mediated migration in bovine aortic and murine embryonic endothelial cells (37).…”

Section: Discussionsupporting

confidence: 88%

“…More recently, BMP9 and BMP10 have been identified as ALK1 ligands, stimulating the Smad1/5/8 pathway and transcription of the Id genes (22)(23)(24). BMP9/10 signaling may underlie the potent induction of genes such as IL8 by a constitutively active ALK1 receptor, but not by TGF␤ 1 , in endothelial cells (25). These new insights into ALK1 function in the endothelium have led to a more BMP-centered hypothesis of vascular dysfunction in HHT (26).…”

mentioning

confidence: 99%

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Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial Cells

Upton

Davies

Trembath

et al. 2009

Journal of Biological Chemistry

186

192

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Mutations in transforming growth factor-␤ (TGF-␤ Pulmonary arterial hypertension (PAH)3 and hereditary hemorrhagic telangectasia (HHT) are diseases characterized by dysregulated smooth muscle and endothelial cell proliferation in the pulmonary circulation. In PAH, progressive muscularization of arterial vessels decreases the luminal area and elasticity of these vessels (1). Mutations in the gene (BMPR2) encoding the bone morphogenetic type II receptor (BMPR-II), a member of the transforming growth factor (TGF) receptor superfamily, underlie most familial PAH cases and a quarter of idiopathic PAH cases (2-4). HHT involves a progressive loss of capillaries and the emergence of directly linked dilated arterioles and venules, termed arteriovenous malformations (5). Although this mainly occurs in nasal and dermal blood vessels, pulmonary arteriovenous malformations occur in more than 20% of HHT patients (5, 6). The two main forms of HHT arise due to mutations in two other TGF receptor superfamily members, endoglin (HHT1) and ALK1 (HHT2) (7,8). Although the pathologies of PAH and HHT differ, mutations in ALK1 are associated with severe PAH in some HHT2 families, suggesting overlapping characteristics (9 -11). HHT1 is not associated with PAH, but pulmonary arteriovenous malformations are more prevalent than in HHT2 patients (5).TGF␤ superfamily receptors form heteromeric receptor complexes of type I and type II receptors in combinations that dictate the ligand selectivity of the complex (12). There are 7 known type I receptors (ALK1-7) and 5 type II receptors (ActR-II, ActR-IIB, BMPR-II, TGF␤R-II, and AMHR-II). Activated BMP receptors mediate signaling via C-terminal phosphorylation of the receptor Smad (R-Smad) proteins, Smad1, Smad5,. In contrast, TGF␤ receptors typically phosphorylate and activate Smad2 and Smad3. Upon phosphorylation, both the BMP and TGF␤ R-Smads associate with the co-Smad, Smad4, and the R-Smad⅐Smad4 complex translocates and associates with other specific transcription factors to modulate the expression of specific genes (16 -19).ALK1, in complex with ALK5 and TGF␤R-II in endothelial cells, is reported to mediate TGF␤ receptor signaling via the Smad1/5/8 pathway rather than the Smad2/3 pathway (20, 21). More recently, BMP9 and BMP10 have been identified as ALK1 ligands, stimulating the Smad1/5/8 pathway and transcription

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial Cells

Upton

Davies

Trembath

et al. 2009

Journal of Biological Chemistry

186

192

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“…Lux et al studied gene expression in several lines of ECs downstream of low or high concentrations of TGF␤ and CA-Alk1 and found a poor correlation. 111 For example, Id1 was induced in 3 lines of ECs by CA-Alk1 but was downregulated in HMECs by low concentrations of TGF␤ and was unaffected by high concentrations.…”

Section: Role Of Tgf␤ In Vascular Morphogenesismentioning

confidence: 99%

“…VEGF signaling in the formerly trailing/trunk cell now switches from promoting proliferation to promoting migration and the expression of dll4, and this cell now becomes a new tip cell. TGF␤ also promotes migration of the tip cell directly through induction of Id1, 111 whereas BMP signaling induces guidance molecules such as ephrin B1, ephrin B2, EphA4, and Sema3c. 122 We speculate that whereas TGF␤ (along with VEGF) is stimulating a tip cell to migrate, dll4 is maintained in the area of tip cell-trunk cell contact by interaction with MAGI proteins in adherens junctions.…”

Section: Regulation Of Retinal Angiogenesis By Coupled Feedback Loops?mentioning

confidence: 99%

Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-β in Vascular Morphogenesis

Holderfield

Hughes

2008

Circulation Research

289

223

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Abstract-Vascular morphogenesis encompasses a temporally regulated set of morphological changes that endothelial cellsundergo to generate a network of interconnected tubules. Such a complex process inevitably involves multiple cell signaling pathways that must be tightly coordinated in time and space. The formation of a new capillary involves endothelial cell activation, migration, alignment, proliferation, tube formation, branching, anastomosis, and maturation of intercellular junctions and the surrounding basement membrane. Each of these stages is either known or suspected to fall under the influence of the vascular endothelial growth factor, notch, and transforming growth factor-␤/bone morphogenetic protein signaling pathways. Vascular endothelial growth factor is essential for initiation of angiogenic sprouting, and also regulates migration of capillary tip cells, proliferation of trunk cells, and gene expression in both. Notch has been implicated in the regulation of cell fate decisions in the vasculature, especially the choice between arterial and venular endothelial cells, and between tip and trunk cell phenotype. Transforming growth factor-␤ regulates cell migration and proliferation, as well as matrix synthesis. In this review, we emphasize how crosstalk between these pathways is essential for proper patterning of the vasculature and offer a transcriptional oscillator model to explain how these pathways might interact to generate new tip cells during retinal angiogenesis. (Circ Res. 2008;102:637-652.)

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“…ALK1 plays an important role during vascular development and is preferentially expressed on endothelial cells as well as various solid human tumors, including melanoma, breast, lung, prostate, and hepatocellular carcinoma (Lux et al, 1999(Lux et al, , 2006Oh et al, 2000;Goumans et al, 2009). The expression of ALK1 is more markedly up-regulated in tumor-associated vascular endothelial cells compared with normal tissues.…”

Section: Introductionmentioning

confidence: 99%

A Model-Based Approach to Predicting the Human Pharmacokinetics of a Monoclonal Antibody Exhibiting Target-Mediated Drug Disposition

Luu¹,

Bergqvist²,

Chen³

et al. 2012

J Pharmacol Exp Ther

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In the drug discovery and development setting, the ability to accurately predict the human pharmacokinetics (PK) of a candidate compound from preclinical data is critical for informing the effective design of the first-in-human trial. PK prediction is especially challenging for monoclonal antibodies exhibiting nonlinear PK attributed to target-mediated drug disposition (TMDD). Here, we present a model-based method for predicting the PK of PF-03446962, an IgG2 antibody directed against human ALK1 (activin receptor-like kinase 1) receptor. Systems parameters as determined experimentally or obtained from the literature, such as binding affinity (k on and k off ), internalization of the drug-target complex (k int ), target degradation rate (k deg ), and target abundance (R 0 ), were directly integrated into the modeling and prediction. NONMEM 7 was used to model monkey PK data and simulate human PK profiles based on the construct of a TMDD model using a population-based approach. As validated by actual patient data from a phase I study, the human PK of PF-03446962 were predicted within 1-to 2-fold of observations. Whereas traditional approaches fail, this approach successfully predicted the human PK of a monoclonal antibody exhibiting nonlinearity because of TMDD.

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ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-β and constitutively active receptor induced gene expression

Cited by 36 publications

References 95 publications

Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial Cells

Bone Morphogenetic Protein (BMP) and Activin Type II Receptors Balance BMP9 Signals Mediated by Activin Receptor-like Kinase-1 in Human Pulmonary Artery Endothelial Cells

Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-β in Vascular Morphogenesis

A Model-Based Approach to Predicting the Human Pharmacokinetics of a Monoclonal Antibody Exhibiting Target-Mediated Drug Disposition

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