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J. Biol. Chem., Vol. 281, Issue 16, 10883-10889, April 21, 2006

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Insulin-like Growth Factor-binding Protein-5 Activates Plasminogen by Interaction with Tissue Plasminogen Activator, Independently of Its Ability to Bind to Plasminogen Activator Inhibitor-1, Insulin-like Growth Factor-I, or Heparin^*

Alice M. Sorrell¹, John H. Shand, Elizabeth Tonner, Matteo Gamberoni, Pier A. Accorsi, James Beattie, Gordon J. Allan, and David J. Flint²

From the Hannah Research Institute, Ayr KA6 5HL, United Kingdom and Dipartimento di Morfofisiologia Veterinaria e Produzioni Animali, Facolta di Medicina Veterinaria, Universita di Bologna, Via Tolara di Sopra 50, 40064 Ozzano Emilia (BO), Italy

Transgenic mice expressing IGFBP-5 in the mammary gland exhibit increased cell death and plasmin generation. Because IGFBP-5 has been reported to bind to plasminogen activator inhibitor-1 (PAI-1), we determined the effects of this interaction in HC11 cells. PAI-1 prevented plasmin generation from plasminogen and inhibited cleavage of focal adhesions, expression of caspase 3, and cell death. IGFBP-5 could in turn prevent the effects of PAI-1. IGFBP-5 mutants with reduced affinity for IGF-I (N-term) or deficient in heparin binding (HEP– and C-term E and F) were also effective. This was surprising because IGFBP-5 reportedly interacts with PAI-1 via its heparin-binding domain. Biosensor analysis confirmed that, although wild-type IGFBP-5 and N-term both bound to PAI-1, the C-term E had greatly decreased interaction with PAI-1. This suggests that IGFBP-5 does not antagonize the actions of PAI-1 by a direct molecular interaction. In a cell-free system, using tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) to activate plasminogen, PAI-1 inhibited plasmin generation induced by both activators, whereas IGFBP-5 prevented the effects of PAI-1 on tPA but not uPA. Furthermore, we noted that IGFBP-5 activated plasminogen to a greater extent than could be explained solely by inhibition of PAI-1, suggesting that IGFBP-5 could directly activate tPA. Indeed, IGFBP-5 and the C-term E and F were all able to enhance the activity of tPA but not uPA. These data demonstrate that IGFBP-5 can enhance the activity of tPA and that this can result in cell death induced by cleavage of focal adhesions. Thus IGFBP-5 can induce cell death by both sequestering IGF-I and enhancing plasmin generation.

Received for publication, August 3, 2005 , and in revised form, February 16, 2006.

^* This work was supported in part by the Scottish Executive Environment and Rural Affairs Department. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the British Council in Korea through the Chevening Scholarship Scheme.

² To whom correspondence should be addressed: Hannah Research Institute, Ayr KA6 5HL, United Kingdom. Tel.: 44-1292-674044; Fax: 44-1292-674004; E-mail: d.flint{at}hannah.ac.uk.

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