Heparin II domain of fibronectin mediates contractility through an α4β1 co-signaling pathway

Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI 53706, USA.
Experimental Cell Research (Impact Factor: 3.25). 03/2010; 316(9):1500-12. DOI: 10.1016/j.yexcr.2010.03.010
Source: PubMed


In the trabecular meshwork (TM) of the eye, regulation of tissue contractility by the PPRARI sequence within the Heparin II (HepII) domain of fibronectin is believed to control the movement of aqueous humor and dictate the level of intraocular pressure. This study shows that the HepII domain utilizes activated alpha4beta1 integrin and collagen to mediate a co-signaling pathway that down-regulates contractility in TM cells. siRNA silencing of alpha4beta1 integrin blocked the actin disrupting effects of both PPRARI and the HepII domain. The down-regulation of the actin cytoskeleton and contractility did not involve syndecan-4 or other heparan sulfate proteoglycans (HSPGs) since siRNA silencing of syndecan-4 expression or heparitinase removal of cell surface HSPGs did not prevent the HepII-mediated disruption of the actin cytoskeleton. HepII-mediated disruption of the cytoskeleton depended upon the presence of collagen in the extracellular matrix, and cell binding studies indicated that HepII signaling involved cross-talk between alpha4beta1 and alpha1/alpha2beta1 integrins. This is the first time that the PPRARI sequence in the HepII domain has been shown to serve as a physiological alpha4beta1 ligand, suggesting that alpha4beta1 integrin may be a key regulator of tissue contractility.

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Available from: Nader Sheibani, Dec 23, 2013
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    • "It has been found that the active site in the heparin II (HepII) domain of fibronectin could regulate outflow facility in cultured anterior segment and disrupt actin cytoskeleton in transformed human TM (TM-1) cells, and the active site in the HepII domain is the syndecan/integrin binding sequence, PPRARI [72]. The PPRARI sequence in the HepII domain has been shown to serve as a physiological α4β1 ligand [73], and soluble anti-α4 integrin antibodies could inhibit Hep II domain-mediated cell spreading and soluble vascular cell adhesion molecule-1- (α4β1-ligand) induced cell spreading, which suggests the Hep II domain mediates cell spreading and stress fiber formation through α4β1 integrin, a potentially key regulator of tissue contractility [74]. Recently, it has been reported that β1 integrin function-blocking antibody inhibits adhesion and spread of TM cells on Galectin-8- (Gal8-) coated wells. "
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