TF/FVIIa Transactivate PDGFRβ to Regulate PDGF-BB–Induced Chemotaxis in Different Cell Types

Siegbahn, Agneta; Johnell, Matilda; Nordin, Anna; Åberg, Mikael; Velling, Teet

doi:10.1161/atvbaha.107.155754

Cited by 39 publications

(43 citation statements)

References 46 publications

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“…These conclusions are in agreement with recent studies carried out under in vitro conditions that support an involvement of PAR-2 signalling in: 1) fibroblast recruitment and proliferation (through PDGF, TGF-a and MMP9 upregulation, and TGF-b activation by MMP9) [35][36][37], 2) fibroblast/SMC transaction (through PDGF and TGF-b hyper-expression and activation) [27,28], 3) SMC proliferation (through PDGF) [35,36] and 4) SMC activation and vessel contraction (through TGF-b upregulated ET-1) [38,39].…”

Section: Discussionsupporting

confidence: 93%

Pulmonary hypertension in smoking mice over-expressing protease-activated receptor-2

Cunto¹,

Cardini²,

Cirino³

et al. 2010

Eur Respir J

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The mechanism(s) involved in the development of pulmonary hypertension (PH) in COPD is still the object of investigation. Cigarette smoke (CS) may lead to remodelling of intrapulmonary vessels and dynamic changes in vascular function, at least in some smokers. A role for proteases in PH has been recently put forward.We investigated, in smoking mice, the role of protease-activated receptor (PAR)-2 in the pathogenesis of PH associated with emphysema.We demonstrated that CS exposure can modulate PAR-2 expression in mouse lung. Acute CS exposure induces in wildtype (WT) and in transgenic mice over-expressing PAR-2 (FVB PAR-2-TgN ) a similar degree of neutrophil influx in bronchoalveolar lavage fluids. After chronic CS exposure WT and FVB PAR-2-TgN mice show emphysema, but only transgenic mice develop muscularisation of small intrapulmonary vessels that precedes the development of PH (,45% increase) and right ventricular hypertrophy. Smoking in FVB PAR-2-TgN mice results in an imbalance between vasoconstrictors (especially endothelin-1) and vasodilators (i.e. vascular endothelial growth factor, endothelial nitric oxide synthase and inducible nitric oxide synthase) and enhanced production of growth factors involved both in fibroblast-smooth muscle cell transaction (i.e. platelet-derived growth factor (PDGF) and transforming growth factor b) and vascular cell proliferation (PDGF). PAR-2 signalling can influence the production and release of many factors, which may play a role in the development of PH in smokers.

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Section: Discussionsupporting

confidence: 93%

Pulmonary hypertension in smoking mice over-expressing protease-activated receptor-2

Cunto¹,

Cardini²,

Cirino³

et al. 2010

Eur Respir J

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“…This is likely due to contamination of the antibodies with PDGF, which is released in serum in massive amounts by activated platelets, and with other molecules that are able to indirectly activate PDGFRs. This process, known as receptor transactivation, can be triggered by angiotensin II, inflammatory cytokines, drugs, and many other factors (25)(26)(27)(28). Such contaminants are difficult to trace because they are highly variable in terms of chemical structure and are active at low concentrations.…”

Section: Discussionmentioning

confidence: 99%

Lack of evidence of stimulatory autoantibodies to platelet‐derived growth factor receptor in patients with systemic sclerosis

Classen¹,

Henrohn²,

Rorsman³

et al. 2009

Arthritis & Rheumatism

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Objective. Systemic sclerosis (SSc) is a severe connective tissue disease of unknown etiology, characterized by fibrosis of the skin and multiple internal organs. Recent findings suggested that the disease is driven by stimulatory autoantibodies to platelet-derived growth factor receptor (PDGFR), which stimulate the production of reactive oxygen species (ROS) and collagen by fibroblasts. These results opened novel avenues of research into the diagnosis and treatment of SSc. The present study was undertaken to confirm the presence of anti-PDGFR antibodies in patients with SSc.Methods. Immunoglobulins from 37 patients with SSc were purified by protein A/G chromatography. PDGFR activation was tested using 4 different sensitive bioassays, i.e., cell proliferation, ROS production, signal transduction, and receptor phosphorylation; the latter was also tested in a separate population of 7 patients with SSc from a different research center.Results. Purified IgG samples from patients with SSc were positive when tested for antinuclear autoantibodies, but did not specifically activate PDGFR␣ or PDGFR␤ in any of the tests. Cell stimulation with PDGF itself consistently produced a strong signal.Conclusion. The present results raise questions regarding the existence of agonistic autoantibodies to PDGFR in SSc.

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“…While indirect activation of growth factor receptors (also called transactivation) has been reported, and the mechanism by which indirect activation proceeds has been studied (14,25,28,37,44,45,50,58,60), little is known regarding how an indirectly activated receptor propagates intracellular signaling events (7). Since such signaling is tightly associated with pathology (41), identification of the key players and pathways was an opportunity to build the conceptual foundation necessary to develop effective therapeutic options for individuals afflicted by PVR.…”

mentioning

confidence: 99%

Pathological Signaling via Platelet-Derived Growth Factor Receptor α Involves Chronic Activation of Akt and Suppression of p53

Lei

Velez²,

Kazlauskas

2011

Molecular and Cellular Biology

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In contrast to direct activation of platelet-derived growth factor (PDGF) receptor ␣ (PDGFR␣) via PDGF, indirect activation via growth factors outside the PDGF family failed to induce dimerization, internalization, and degradation of PDGFR␣. Chronically activated, monomeric PDGFR␣ induced prolonged activation of Akt and suppressed the level of p53. These events were sufficient to promote both cellular responses (proliferation, survival, and contraction) that are intrinsic to proliferative vitreoretinopathy (PVR) and induce the disease itself. This signature signaling pathway appeared to extend beyond PVR since deregulating PDGFR␣ in ways that promote solid tumors also resulted in chronic activation of Akt and a decline in the level of p53.

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TF/FVIIa Transactivate PDGFRβ to Regulate PDGF-BB–Induced Chemotaxis in Different Cell Types

Cited by 39 publications

References 46 publications

Pulmonary hypertension in smoking mice over-expressing protease-activated receptor-2

Pulmonary hypertension in smoking mice over-expressing protease-activated receptor-2

Lack of evidence of stimulatory autoantibodies to platelet‐derived growth factor receptor in patients with systemic sclerosis

Pathological Signaling via Platelet-Derived Growth Factor Receptor α Involves Chronic Activation of Akt and Suppression of p53

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