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Blood, 1 July 2008, Vol. 112, No. 1, pp. 8. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Gonias, S. L. PubMed PubMed Citation Articles by Gonias, S. L. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS Comment on Stepanova et al, page 100 Urokinase: the identity crisis continues Steven L. Gonias UNIVERSITY OF CALIFORNIA AT SAN DIEGO Although urokinase-type plasminogen activator (uPA) was first identified due to its role in fibrinolysis, new studies increasingly uncover novel mechanisms by which uPA may regulate cell physiology. In this issue of Blood, Stepanova and colleagues demonstrate that binding of single-chain uPA to nucleolin facilitates nuclear translocation of uPA and promotes expression of smooth muscle -actin (-SMA). In many multidomain proteases, exosites regulate protease activity by facilitating zymogen activation, controlling reaction with inhibitors, and localizing the protease with substrates. However, in some proteases, the enzyme active site may be regulatory, and the principal function may be something other than peptide-bond hydrolysis. uPA was first identified as 1 of 2 major mammalian plasminogen activators. The function of uPA in fibrinolysis is supported by the observation that simultaneous deletion of the genes for uPA and tissue-type plasminogen activator (tPA) in mice causes more severe thrombosis than tPA deletion alone.1 The activity of uPA is intimately linked with that of its primary cell-surface receptor, uPAR. uPA-binding to uPAR, which requires the N-terminal EGF-like domain in uPA, mobilizes a cascade of cell-surface proteases that may support cell migration and tissue remodeling. Furthermore, uPA-binding to uPAR triggers cell signaling to factors such as ERK/MAP kinase and Akt.2 Regulation of cell signaling downstream of uPAR has been implicated in cell migration, cell survival, gene transcription, and processes integral to cancer progression, such as epithelial-mesenchymal transition.3 The low-density lipoprotein receptor–related protein (LRP-1) functions as a second uPA receptor, albeit with lower affinity. The principal function of LRP-1 in regulating uPA probably involves endocytosis and catabolism; however, LRP-1 also controls cell signaling in response to uPA-Serpin complexes.4 The interaction of single-chain uPA with nucleolin, as described by Stepanova and colleagues, represents a novel pathway by which uPA may regulate cell physiology. Their biochemical and imaging studies provide compelling evidence that nucleolin shuttles intact single-chain uPA to the nucleus. Nuclear translocation of uPA appears to be necessary for regulating the expression of -SMA, a marker of myofibroblasts implicated in processes such as pulmonary fibrosis and atherosclerosis.5 Thus, in a manner reminiscent of thrombin, the interaction of uPA with cells may involve a menu of receptors and path-ways. Based on KD values, one might argue that binding of uPA to uPAR should be favored; however, biochemistry occurring at the cell surface is not an equilibrium system, and many high-affinity interactions are dominated by slow off-rate constants. How might the pathway selected by uPA be regulated? The authors show that mild acidification decreases the binding affinity of uPA for uPAR almost 10-fold while increasing the binding affinity for nucleolin. They argue that this shift may favor uPA association with nucleolin in endosomes. Although this is plausible, one must also consider the extracellular tumor microenvironment and its propensity for acidification.6 Finally, the fact that 2-chain uPA does not localize to the nucleus emphasizes the importance of understanding various regions in the structure of uPA that are cleaved by plasmin, converting single-chain uPA into 2-chain uPA, high-molecular-weight uPA into low-molecular-weight uPA, and deleting the EGF-like domain.7 These reactions may play a pivotal role in controlling how uPA affects cell physiology. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Carmeliet P, Schoonjans L, Ream B, et al. Physiologic consequences of loss of plasminogen activator gene function in mice. Nature. 1994;368:419–424.[CrossRef][Medline] [Order article via Infotrieve] Blasi F, Carmeliet P. uPAR: a versatile signaling orchestrator. Nat Rev Mol Cell Biol. 2002;3:932–943.[CrossRef][Medline] [Order article via Infotrieve] Lester RD, Jo M, Montel V, et al. uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J Cell Biol. 2007;178:425–436.[Abstract/Free Full Text] Webb DJ, Thomas KS, Gonias SL. Plasminogen activator inhibitor 1 functions as a urokinase response modifier at the level of cell signaling and thereby promotes MCF-7 cell growth. J Cell Biol. 2001;152:741–752.[Abstract/Free Full Text] Hinz B, Phan SH, Thannickal VJ. The Myofibroblast: one function, multiple origins. Am J Pathol. 2007;170:1807–1816.[Abstract/Free Full Text] Tredan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst. 2007;99:1441–1451.[Abstract/Free Full Text] de Munk GAW, Rijken DC. Fibrinolytic properties of single chain urokinase-type plasminogen activator (pro-urokinase). Fibrinolysis. 1990;4:1–9. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Nuclear translocation of urokinase-type plasminogen activator Victoria Stepanova, Tatiana Lebedeva, Alice Kuo, Serge Yarovoi, Sergei Tkachuk, Sergei Zaitsev, Khalil Bdeir, Inna Dumler, Michael S. Marks, Yelena Parfyonova, Vsevolod A. Tkachuk, Abd Al-Roof Higazi, and Douglas B. Cines Blood 2008 112: 100-110. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Gonias, S. L. PubMed PubMed Citation Articles by Gonias, S. L. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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