Inhibition of receptor-dependent urokinase signaling by specific Ser to Glu substitutions

Biological Chemistry
Maria V CarrieroM Patrizia Stoppelli

Abstract

We have previously reported that phosphorylation of human urokinase on Ser138/303 abolishes its catalytic-independent motogen and proadhesive abilities, whereas receptor binding is not affected. Here we show that substitution of the two relevant serines with glutamic acid residues impairs the ability of urokinase to mobilize a variety of human and mouse cell lines as well as human primary T lymphocytes. Accordingly, urokinase receptor-dependent signaling, leading to cytoskeletal rearrangements and paxillin re-distribution, does not occur in MCF-7 breast carcinoma cells exposed to 'phosphorylation-like' urokinase. Unlike the wild-type form, di-substituted urokinase is unable to induce the physical association of urokinase receptor with alphavbeta5 vitronectin receptor, which is required for MCF-7 urokinase-dependent cell migration. Finally, the di-substituted variant fails to activate p55fgr, a member of the Src tyrosine kinase family, which mediates cell migration and adhesion of U937 myelomonocytic cells. In conclusion, the finding that specific amino acid substitutions strongly interfere with the ability of urokinase to stimulate cell migration, and the associated intracellular events uncover a novel way to regulate urokinase...Continue Reading

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Citations

Oct 11, 2008·International Journal of Cancer. Journal International Du Cancer·Immacolata VoccaMaria Patrizia Stoppelli
Apr 15, 2015·Frontiers in Immunology·Malcolm Finlayson
Nov 26, 2002·International Journal of Cancer. Journal International Du Cancer·Immacolata SilvestriMaria Vincenza Carriero
May 4, 2005·The Journal of Biological Chemistry·Lucia GargiuloMaria V Carriero
Mar 23, 2013·Chembiochem : a European Journal of Chemical Biology·Paola FrancoMaria Patrizia Stoppelli

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