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

The Journal of Biological Chemistry
Alice M SorrellD J Flint

Abstract

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 pla...Continue Reading

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Citations

Nov 11, 2008·Journal of Mammary Gland Biology and Neoplasia·D J FlintG J Allan
Nov 26, 2008·Journal of Mammary Gland Biology and Neoplasia·Claire M Perks, Jeff M P Holly
Oct 19, 2006·Neuroendocrinology·Jeff Holly, Claire Perks
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Jul 21, 2009·Biochemical Society Transactions·Angara SureshbabuDavid J Flint
Sep 14, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Lasse Bach SteffensenClaus Oxvig
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