Density enhanced phosphatase-1 down-regulates urokinase receptor surface expression in confluent endothelial cells

Brunner, Patrick M.; Heier, Patricia C.; Mihály-Bison, Judit; Priglinger, Ute; Binder, Bernd R.; Prager, Gerald W.

doi:10.1182/blood-2010-09-307694

Cited by 31 publications

(29 citation statements)

References 47 publications

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“…In fact, the role of an miRNA in a pathological context is also dependent on the relative expression levels of its targets in the tissue under examination [47]. However, in epithelium-derived cells, miR-328 increases cell proliferation (our results) and cell migration [44], and this is in line with the opposing role played by PTPRJ in these processes [10][11][12][13][14][15]48,49].…”

Section: Discussionsupporting

confidence: 66%

Protein tyrosine phosphatase PTPRJ is negatively regulated by microRNA‐328

Paduano¹,

Dattilo²,

Narciso³

et al. 2012

The FEBS Journal

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Expression of PTPRJ, which is a ubiquitous receptor-type protein tyrosine phosphatase, is significantly reduced in a vast majority of human epithelial cancers and cancer cell lines (i.e. colon, lung, thyroid, mammary and pancreatic tumours). A possible role for microRNAs (miRNAs) in the negative regulation of PTPRJ expression has never been investigated. In this study, we show that overexpression of microRNA-328 (miR-328) decreases PTPRJ expression in HeLa and SKBr3 cells. Further investigations demonstrate that miR-328 acts directly on the 3¢UTR of PTPRJ, resulting in reduced mRNA levels. Luciferase assay and site-specific mutagenesis were used to identify a functional miRNA response element in the 3¢UTR of PTPRJ. Expression of miR-328 significantly enhances cell proliferation in HeLa and SKBr3 cells, similar to the effects of downregulation of PTPRJ with small interfering RNA. Additionally, in HeLa cells, the proliferative effect of miR-328 was not observed when PTPRJ was silenced with small interfering RNA; conversely, restoration of PTPRJ expression in miR-328-overexpressing cells abolished the proliferative activity of miR-328. In conclusion, we report the identification of miR-328 as an important player in the regulation of PTPRJ expression, and we propose that the interaction of miR-328 with PTPRJ is responsible for miR-328-dependent increase of epithelial cell proliferation.

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Section: Discussionsupporting

confidence: 66%

Protein tyrosine phosphatase PTPRJ is negatively regulated by microRNA‐328

Paduano¹,

Dattilo²,

Narciso³

et al. 2012

The FEBS Journal

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“…Despite reports highlighting inhibitory roles for DEP-1 in endothelial cell proliferation and capillary formation (3,43,44), our group previously showed that endogenously expressed DEP-1 in nonquiescent endothelial cells positively regulates Src activation, cell invasion, permeability, and capillary formation (14,15,19). We now show that VEGFinduced permeability (Fig.…”

Section: Discussionmentioning

confidence: 53%

Tyrosine Phosphatase PTPRJ/DEP-1 Is an Essential Promoter of Vascular Permeability, Angiogenesis, and Tumor Progression

et al. 2016

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The protein tyrosine phosphatase PTPRJ/DEP-1 has been implicated in negative growth regulation in endothelial cells, where its expression varies at transitions between proliferation and contact inhibition. However, in the same cells, DEP-1 has also been implicated in VEGF-dependent Src activation, permeability, and capillary formation, suggesting a positive role in regulating these functions. To resolve this dichotomy in vivo, we investigated postnatal angiogenesis and vascular permeability in a DEP-1-deficient mouse. In this study, we report that DEP-1 is required for Src activation and phosphorylation of its endothelial cell-specific substrate, VE-cadherin, after systemic injection of VEGF. Accordingly, VEGF-induced vascular leakage was abrogated in the DEP-1-deficient mice. Furthermore, capillary formation was impaired in murine aortic tissue rings or Matrigel plugs infused with VEGF. In the absence of DEP-1, angiogenesis triggered by ischemia or during tumor formation was defective, which in the latter case was associated with reduced tumor cell proliferation and increased apoptosis. Macrophage infiltration was also impaired, reflecting reduced vascular permeability in the tumors or a possible cell autonomous effect of DEP-1. Consequently, the formation of spontaneous and experimental lung metastases was strongly decreased in DEP-1-deficient mice. In clinical specimens of cancer, less vascularized tumors exhibited lower microvascular expression of DEP-1. Altogether, our results established DEP-1 as an essential driver of VEGF-dependent permeability, angiogenesis, and metastasis, suggesting a novel therapeutic route to cancer treatment. Cancer Res; 76(17); 5080-91. Ó2016 AACR.

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“…Through interaction with vitronectin (VN), uPAR influences EC motility and migration along an ECM substratum [50]. PAI-1 has been shown to control MC motility by a similar VN-dependent mechanism [51], [52]. PAI-1 also regulates protease secretion and thus may influence the proteolytic balance of the system.…”

Section: Methodsmentioning

confidence: 99%

A Computational Model Predicting Disruption of Blood Vessel Development

et al. 2013

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Vascular development is a complex process regulated by dynamic biological networks that vary in topology and state across different tissues and developmental stages. Signals regulating de novo blood vessel formation (vasculogenesis) and remodeling (angiogenesis) come from a variety of biological pathways linked to endothelial cell (EC) behavior, extracellular matrix (ECM) remodeling and the local generation of chemokines and growth factors. Simulating these interactions at a systems level requires sufficient biological detail about the relevant molecular pathways and associated cellular behaviors, and tractable computational models that offset mathematical and biological complexity. Here, we describe a novel multicellular agent-based model of vasculogenesis using the CompuCell3D (http://www.compucell3d.org/) modeling environment supplemented with semi-automatic knowledgebase creation. The model incorporates vascular endothelial growth factor signals, pro- and anti-angiogenic inflammatory chemokine signals, and the plasminogen activating system of enzymes and proteases linked to ECM interactions, to simulate nascent EC organization, growth and remodeling. The model was shown to recapitulate stereotypical capillary plexus formation and structural emergence of non-coded cellular behaviors, such as a heterologous bridging phenomenon linking endothelial tip cells together during formation of polygonal endothelial cords. Molecular targets in the computational model were mapped to signatures of vascular disruption derived from in vitro chemical profiling using the EPA's ToxCast high-throughput screening (HTS) dataset. Simulating the HTS data with the cell-agent based model of vascular development predicted adverse effects of a reference anti-angiogenic thalidomide analog, 5HPP-33, on in vitro angiogenesis with respect to both concentration-response and morphological consequences. These findings support the utility of cell agent-based models for simulating a morphogenetic series of events and for the first time demonstrate the applicability of these models for predictive toxicology.

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Density enhanced phosphatase-1 down-regulates urokinase receptor surface expression in confluent endothelial cells

Cited by 31 publications

References 47 publications

Protein tyrosine phosphatase PTPRJ is negatively regulated by microRNA‐328

Protein tyrosine phosphatase PTPRJ is negatively regulated by microRNA‐328

Tyrosine Phosphatase PTPRJ/DEP-1 Is an Essential Promoter of Vascular Permeability, Angiogenesis, and Tumor Progression

A Computational Model Predicting Disruption of Blood Vessel Development

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