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Open AccessArticle

A Matricryptic Conformation of the Integrin-Binding Domain of Fibronectin Regulates Platelet-Derived Growth Factor-Induced Intracellular Calcium Release

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Department of Biomedical Engineering, University of Rochester, Rochester, NY 14627, USA
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Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
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Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
*
Author to whom correspondence should be addressed.
Cells 2019, 8(11), 1351; https://doi.org/10.3390/cells8111351
Received: 7 October 2019 / Revised: 24 October 2019 / Accepted: 29 October 2019 / Published: 30 October 2019
(This article belongs to the Special Issue Fibronectin in Health and Diseases)
Platelet-derived growth factor (PDGF) signaling is dysregulated in a wide variety of diseases, making PDGF an attractive therapeutic target. However, PDGF also affects numerous signaling cascades essential for tissue homeostasis, limiting the development of PDGF-based therapies that lack adverse side-effects. Recent studies showed that fibroblast-mediated assembly of extracellular matrix (ECM) fibronectin fibrils attenuates PDGF-induced intracellular calcium release by selectively inhibiting phosphoinositol 3-kinase (PI3K) activation while leaving other PDGF-mediated signaling cascades intact. In the present study, a series of recombinant fibronectin-derived fusion proteins were used to localize the sequences in fibronectin that are responsible for this inhibition. Results demonstrate that attenuation of PDGF-induced intracellular calcium release by the fibronectin matrix mimetic, FNIII1H,8-10 requires α5β1 integrin ligation, but is not dependent upon the matricryptic, heparin-binding site of FNIII1. Intact cell-binding fibronectin fragments were also unable to attenuate PDGF-induced intracellular calcium release. In contrast, a novel integrin-binding fragment that adopts an extended and aligned conformational state, inhibited both PI3K activation and intracellular calcium release in response to PDGF. Taken together, these studies provide evidence that attenuation of PDGF-induced intracellular calcium release by fibronectin is mediated by a novel conformation of the α5β1 integrin-binding, FNIII9-10 modules, that is expressed by fibrillar fibronectin. View Full-Text
Keywords: extracellular matrix; calcium; phosphoinositide 3-kinase; growth factors; integrin; molecular dynamics simulations extracellular matrix; calcium; phosphoinositide 3-kinase; growth factors; integrin; molecular dynamics simulations
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Farrar, C.S.; Rouin, G.T.; Miller, B.L.; Raeman, C.H.; Mooney, N.A.; Hocking, D.C. A Matricryptic Conformation of the Integrin-Binding Domain of Fibronectin Regulates Platelet-Derived Growth Factor-Induced Intracellular Calcium Release. Cells 2019, 8, 1351.

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