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Vol. 20, Issue 3, 745-756, February 1, 2009

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Mannose 6-Phosphate/Insulin-like Growth Factor 2 Receptor Limits Cell Invasion by Controlling Vβ3 Integrin Expression and Proteolytic Processing of Urokinase-type Plasminogen Activator Receptor

Herbert B. Schiller^*, Andreas Szekeres^*, Bernd R. Binder, Hannes Stockinger^*, and Vladimir Leksa^*,

*Department of Molecular Immunology, Center for Physiology, Pathophysiology and Immunology, Medical University of Vienna, A-1090 Vienna, Austria; Department of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine, Medical University of Vienna, A-1090 Vienna, Austria; and Institute of Molecular Biology, Slovak Academy of Sciences, 845 51 Bratislava, Slovak Republic

Submitted June 6, 2008; Revised October 27, 2008; Accepted November 18, 2008
Monitoring Editor: M. Bishr Omary

The multifunctional mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) is considered a tumor suppressor. We report here that RNA interference with M6P/IGF2R expression in urokinase-type plasminogen activator (uPA)/urokinase-type plasminogen activator receptor (uPAR) expressing human cancer and endothelial cells resulted in increased pericellular plasminogen activation, cell adhesion, and higher invasive potential through matrigel. M6P/IGF2R silencing led also to the cell surface accumulation of urokinase and plasminogen and enhanced expression of V integrins. Genetic rescue experiments and inhibitor studies revealed that the enhanced plasminogen activation was due to a direct effect of M6P/IGF2R on uPAR, whereas increased cell adhesion to vitronectin was dependent on V integrin expression and not uPAR. Increased cell invasion of M6P/IGF2R knockdown cells was rescued by cosilencing both uPAR and V integrin. Furthermore, we found that M6P/IGF2R expression accelerates the cleavage of uPAR. M6P/IGF2R silencing resulted in an increased ratio of full-length uPAR to the truncated D2D3 fragment, incapable of binding most uPAR ligands. We conclude that M6P/IGF2R controls cell invasion by regulating V integrin expression and by accelerating uPAR cleavage, leading to the loss of the urokinase/vitronectin/integrin-binding site on uPAR.

Address correspondence to: Vladimir Leksa (vladimir.leksa{at}meduniwien.ac.at)

Abbreviations used: IGF, insulin-like growth factor; M6P/IGF2R, mannose 6-phosphate/insulin-like growth factor 2 receptor; Plg, plasminogen; PAI, plasminogen activator inhibitor; shRNA, short hairpin RNA; TGF, transforming growth factor; uPA, urokinase-type plasminogen activator; uPAR, urokinase-type plasminogen activator receptor.