Charles Szekeres

Publications (6)42.66 Total impact

• Article: Endothelial alpha3beta1-integrin represses pathological angiogenesis and sustains endothelial-VEGF.

  Rita Graça da Silva, Bernardo Tavora, Stephen D Robinson, Louise E Reynolds, Charles Szekeres, John Lamar, Sílvia Batista, Vassiliki Kostourou, Mitchel A Germain, Andrew R Reynolds, Dylan T Jones, Alan R Watson, Janet L Jones, Adrian Harris, Ian R Hart, M Luisa Iruela-Arispe, C Michael Dipersio, Jordan A Kreidberg, Kairbaan M Hodivala-Dilke
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  ABSTRACT: Integrin alpha3beta1 is a major receptor for laminin. The expression levels of laminins-8 and -10 in the basement membrane surrounding blood vessels are known to change during tumor angiogenesis. Although some studies have suggested that certain ligands of alpha3beta1 can affect angiogenesis either positively or negatively, either a direct in vivo role for alpha3beta1 in this process or its mechanism of action in endothelial cells during angiogenesis is still unknown. Because the global genetic ablation of alpha3-integrin results in an early lethal phenotype, we have generated conditional-knockout mice where alpha3 is deleted specifically in endothelial cells (ec-alpha3-/-). Here we show that ec-alpha3-/- mice are viable, fertile, and display enhanced tumor growth, elevated tumor angiogenesis, augmented hypoxia-induced retinal angiogenesis, and increased vascular endothelial growth factor (VEGF)-mediated neovascularization ex vivo and in vivo. Furthermore, our data provide a novel method by which an integrin may regulate angiogenesis. We show that alpha3beta1 is a positive regulator of endothelial-VEGF and that, surprisingly, the VEGF produced by endothelial cells can actually repress VEGF-receptor 2 (Flk-1) expression. These data, therefore, identify directly that endothelial alpha3beta1 negatively regulates pathological angiogenesis and implicate an unexpected role for low levels of endothelial-VEGF as an activator of neovascularization.
  American Journal Of Pathology 09/2010; 177(3):1534-48. · 4.89 Impact Factor
• Article: Endothelial α3β1Integrin Represses Pathological Angiogenesis and Sustains Endothelial-VEGF

  Rita Graça da Silva, Bernardo Tavora, Stephen D. Robinson, Louise E. Reynolds, Charles Szekeres, John Lamar, Sílvia Batista, Vassiliki Kostourou, Mitchel A. Germain, Andrew R. Reynolds, Dylan T. Jones, Alan R. Watson
  American Journal of Pathology - AMER J PATHOL. 01/2010; 177(3):1534-1548.
• Article: Alpha3beta1 integrin in epidermis promotes wound angiogenesis and keratinocyte-to-endothelial-cell crosstalk through the induction of MRP3.

  Kara Mitchell, Charles Szekeres, Vincenzo Milano, Kimberly B Svenson, Marit Nilsen-Hamilton, Jordan A Kreidberg, C Michael DiPersio
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  ABSTRACT: During cutaneous wound healing, epidermal keratinocytes play essential roles in the secretion of factors that promote angiogenesis. However, specific cues in the wound microenvironment that trigger the production of pro-angiogenic factors by keratinocytes, and the cellular receptors that mediate this response, remain unclear. In this study, we exploited a model of conditional integrin knockout to demonstrate impaired wound angiogenesis in mice that lack alpha3beta1 integrin in epidermis. In addition, we used genetic and shRNA approaches to determine that alpha3beta1-integrin deficiency in keratinocytes leads to reduced mRNA and protein expression of the pro-angiogenic factor mitogen-regulated protein 3 (MRP3; also known as PRL2C4), and to demonstrate that this regulation provides a mechanism of keratinocyte-to-endothelial-cell crosstalk that promotes endothelial-cell migration. Finally, we showed that the impaired wound angiogenesis in epidermis-specific alpha3-integrin-knockout mice is correlated with reduced expression of MRP3 in wounded epidermis. These findings identify a novel role for alpha3beta1 integrin in promoting wound angiogenesis through a mechanism of crosstalk from epidermal to endothelial cells, and they implicate MRP3 in this integrin-dependent crosstalk. Such a mechanism represents a novel paradigm for integrin-mediated regulation of wound angiogenesis that extends beyond traditional roles for integrins in cell adhesion and migration.
  Journal of Cell Science 07/2009; 122(Pt 11):1778-87. · 6.11 Impact Factor
• Source

  Available from: Amelia Stanco

  Article: Netrin-1-alpha3beta1 integrin interactions regulate the migration of interneurons through the cortical marginal zone.

  Amelia Stanco, Charles Szekeres, Nikhil Patel, Sarada Rao, Kenneth Campbell, Jordan A Kreidberg, Franck Polleux, E S Anton
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  ABSTRACT: Cortical GABAergic interneurons, most of which originate in the ganglionic eminences, take distinct tangential migratory trajectories into the developing cerebral cortex. However, the ligand-receptor systems that modulate the tangential migration of distinct groups of interneurons into the emerging cerebral wall remain unclear. Here, we show that netrin-1, a diffusible guidance cue expressed along the migratory routes traversed by GABAergic interneurons, interacts with alpha3beta1 integrin to promote interneuronal migration. In vivo analysis of interneuron-specific alpha3beta1 integrin, netrin-1-deficient mice (alpha3(lox/-)Dlx5/6-CIE, netrin-1(-/-)) reveals specific deficits in the patterns of interneuronal migration along the top of the developing cortical plate, resulting in aberrant interneuronal positioning throughout the cerebral cortex and hippocampus of conditional alpha3(lox/-)Dlx5/6-CIE, netrin-1(-/-) mice. These results indicate that specific guidance mechanisms, such as netrin-1-alpha3beta1 integrin interactions, modulate distinct routes of interneuronal migration and the consequent positioning of groups of cortical interneurons in the developing cerebral cortex.
  Proceedings of the National Academy of Sciences 05/2009; 106(18):7595-600. · 9.68 Impact Factor
• Article: Coordinate integrin and c-Met signaling regulate Wnt gene expression during epithelial morphogenesis.

  Yingjie Liu, Nibedita Chattopadhyay, Shan Qin, Charles Szekeres, Tetyana Vasylyeva, Zhen X Mahoney, Mary Taglienti, Carlton M Bates, Harold A Chapman, Jeffrey H Miner, Jordan A Kreidberg
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  ABSTRACT: Integrin receptors for the extracellular matrix and receptor tyrosine kinase growth factor receptors represent two of the major families of receptors that transduce into cells information about the surrounding environment. Wnt proteins are a major family of signaling molecules that regulate morphogenetic events. There is presently little understanding of how the expression of Wnt genes themselves is regulated. In this study, we demonstrate that alpha3beta1 integrin, a major laminin receptor involved in the development of the kidney, and c-Met, the receptor for hepatocyte growth factor, signal coordinately to regulate the expression of Wnt7b in the mouse. Wnt signals in turn appear to regulate epithelial cell survival in the papilla of the developing kidney, allowing for the elongation of epithelial tubules to form a mature papilla. Together, these results demonstrate how signals from integrins and growth factor receptors can be integrated to regulate the expression of an important family of signaling molecules so as to regulate morphogenetic events.
  Development 02/2009; 136(5):843-53. · 6.60 Impact Factor
• Article: Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis.

  Kevin K Kim, Ying Wei, Charles Szekeres, Matthias C Kugler, Paul J Wolters, Marla L Hill, James A Frank, Alexis N Brumwell, Sarah E Wheeler, Jordan A Kreidberg, Harold A Chapman
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  ABSTRACT: Pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (IPF), results from aberrant wound healing and scarification. One population of fibroblasts involved in the fibrotic process is thought to originate from lung epithelial cells via epithelial-mesenchymal transition (EMT). Indeed, alveolar epithelial cells (AECs) undergo EMT in vivo during experimental fibrosis and ex vivo in response to TGF-beta1. As the ECM critically regulates AEC responses to TGF-beta1, we explored the role of the prominent epithelial integrin alpha3beta1 in experimental fibrosis by generating mice with lung epithelial cell-specific loss of alpha3 integrin expression. These mice had a normal acute response to bleomycin injury, but they exhibited markedly decreased accumulation of lung myofibroblasts and type I collagen and did not progress to fibrosis. Signaling through beta-catenin has been implicated in EMT; we found that in primary AECs, alpha3 integrin was required for beta-catenin phosphorylation at tyrosine residue 654 (Y654), formation of the pY654-beta-catenin/pSmad2 complex, and initiation of EMT, both in vitro and in vivo during the fibrotic phase following bleomycin injury. Finally, analysis of lung tissue from IPF patients revealed the presence of pY654-beta-catenin/pSmad2 complexes and showed accumulation of pY654-beta-catenin in myofibroblasts. These findings demonstrate epithelial integrin-dependent profibrotic crosstalk between beta-catenin and Smad signaling and support the hypothesis that EMT is an important contributor to pathologic fibrosis.
  Journal of Clinical Investigation 01/2009; 119(1):213-24. · 15.39 Impact Factor