Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 311 (5761): 656-659

Copyright © 2006 by the American Association for the Advancement of Science

Structure of Human Urokinase Plasminogen Activator in Complex with Its Receptor

Qing Huai,1 Andrew P. Mazar,2 Alice Kuo,3 Graham C. Parry,2 David E. Shaw,6 Jennifer Callahan,2 Yongdong Li,4 Cai Yuan,4 Chuanbing Bian,4 Liqing Chen,5 Bruce Furie,1 Barbara C. Furie,1 Douglas B. Cines,3 Mingdong Huang1,4*

Abstract: The urokinase plasminogen activator binds to its cellular receptor with high affinity and initiates signaling cascades that are implicated in pathological processes including tumor growth, metastasis, and inflammation. We report the crystal structure at 1.9 angstroms of the urokinase receptor complexed with the urokinase amino-terminal fragment and an antibody against the receptor. The three domains of urokinase receptor form a concave shape with a central cone-shaped cavity where the urokinase fragment inserts. The structure provides insight into the flexibility of the urokinase receptor that enables its interaction with a wide variety of ligands and a basis for the design of urokinase-urokinase receptor antagonists.

1 Division of Hemostasis and Thrombosis, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
2 Attenuon, LLC, 11535 Sorrento Valley Road, Suite 401, San Diego, CA 92121, USA.
3 Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 513A Stellar-Chance, 422 Curie Boulevard, Philadelphia, PA 19104, USA.
4 State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, People's Republic of China.
5 Laboratory for Structural Biology, Department of Chemistry, Graduate Programs of Biotechnology, Chemistry and Materials Science, University of Alabama in Huntsville, Huntsville, AL 35899, USA.
6 D. E. Shaw Research and Development, 39th Floor, Tower 45, 120 West Forty-Fifth Street, New York, NY 10036, USA.

* To whom correspondence should be addressed. E-mail: mhuang1{at}, mhuang{at}

The Urokinase Receptor Homolog Haldisin Is a Novel Differentiation Marker of Stratum Granulosum in Squamous Epithelia.
H. Gardsvoll, M. C. Kriegbaum, E. P. Hertz, W. Alpizar-Alpizar, and M. Ploug (2013)
Journal of Histochemistry & Cytochemistry 61, 802-813
   Abstract »    Full Text »    PDF »
Transgenic chickens expressing human urokinase-type plasminogen activator.
S. H. Lee, M. K. Gupta, Y. T. Ho, T. Kim, and H. T. Lee (2013)
Poultry Science 92, 2396-2403
   Abstract »    Full Text »    PDF »
Domain 2 of uPAR regulates single-chain urokinase-mediated angiogenesis through {beta}1-integrin and VEGFR2.
G. A. LaRusch, A. Merkulova, F. Mahdi, Z. Shariat-Madar, R. G. Sitrin, D. B. Cines, and A. H. Schmaier (2013)
Am J Physiol Heart Circ Physiol 305, H305-H320
   Abstract »    Full Text »    PDF »
A Flexible Multidomain Structure Drives the Function of the Urokinase-type Plasminogen Activator Receptor (uPAR).
H. D. T. Mertens, M. Kjaergaard, S. Mysling, H. Gardsvoll, T. J. D. Jorgensen, D. I. Svergun, and M. Ploug (2012)
J. Biol. Chem. 287, 34304-34315
   Abstract »    Full Text »    PDF »
Urokinase-type Plasminogen Activator-like Proteases in Teleosts Lack Genuine Receptor-binding Epidermal Growth Factor-like Domains.
R. Bager, T. K. Kristensen, J. K. Jensen, A. Szczur, A. Christensen, L. M. Andersen, J. S. Johansen, N. Larsen, E. Baatrup, M. Huang, et al. (2012)
J. Biol. Chem. 287, 27526-27536
   Abstract »    Full Text »    PDF »
Mimicry of the Regulatory Role of Urokinase in Lamellipodia Formation by Introduction of a Non-native Interdomain Disulfide Bond in Its Receptor.
H. Gardsvoll, M. Kjaergaard, B. Jacobsen, M. C. Kriegbaum, M. Huang, and M. Ploug (2011)
J. Biol. Chem. 286, 43515-43526
   Abstract »    Full Text »    PDF »
H. Gardsvoll, B. Jacobsen, M. C. Kriegbaum, N. Behrendt, L. Engelholm, S. Ostergaard, and M. Ploug (2011)
J. Biol. Chem. 286, 33544-33556
   Abstract »    Full Text »    PDF »
Expression of C4.4A, a Structural uPAR Homolog, Reflects Squamous Epithelial Differentiation in the Adult Mouse and during Embryogenesis.
M. C. Kriegbaum, B. Jacobsen, A. Hald, and M. Ploug (2011)
Journal of Histochemistry & Cytochemistry 59, 188-201
   Abstract »    Full Text »    PDF »
Serum-stable RNA aptamers to urokinase-type plasminogen activator blocking receptor binding.
D. M. Dupont, J. B. Madsen, R. K. Hartmann, B. Tavitian, F. Duconge, J. Kjems, and P. A. Andreasen (2010)
RNA 16, 2360-2369
   Abstract »    Full Text »    PDF »
Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation.
B. M. Connolly, E. Y. Choi, H. Gardsvoll, A. L. Bey, B. M. Currie, T. Chavakis, S. Liu, A. Molinolo, M. Ploug, S. H. Leppla, et al. (2010)
Blood 116, 1593-1603
   Abstract »    Full Text »    PDF »
A Cleavage-resistant Urokinase Plasminogen Activator Receptor Exhibits Dysregulated Cell-surface Clearance.
E. C. Nieves and N. Manchanda (2010)
J. Biol. Chem. 285, 12595-12603
   Abstract »    Full Text »    PDF »
Structure-based Engineering of Species Selectivity in the Interaction between Urokinase and Its Receptor: IMPLICATION FOR PRECLINICAL CANCER THERAPY.
L. Lin, H. Gardsvoll, Q. Huai, M. Huang, and M. Ploug (2010)
J. Biol. Chem. 285, 10982-10992
   Abstract »    Full Text »    PDF »
Structure-based design of an urokinase-type plasminogen activator receptor-derived peptide inhibiting cell migration and lung metastasis.
M. V. Carriero, I. Longanesi-Cattani, K. Bifulco, O. Maglio, L. Lista, A. Barbieri, G. Votta, M. T. Masucci, C. Arra, R. Franco, et al. (2009)
Mol. Cancer Ther. 8, 2708-2717
   Abstract »    Full Text »    PDF »
boudin is required for septate junction organisation in Drosophila and codes for a diffusible protein of the Ly6 superfamily.
A. Hijazi, W. Masson, B. Auge, L. Waltzer, M. Haenlin, and F. Roch (2009)
Development 136, 2199-2209
   Abstract »    Full Text »    PDF »
The Urokinase Plasminogen Activator Receptor Promotes Efferocytosis of Apoptotic Cells.
V. D'mello, S. Singh, Y. Wu, and R. B. Birge (2009)
J. Biol. Chem. 284, 17030-17038
   Abstract »    Full Text »    PDF »
Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR.
B. Royer-Zemmour, M. Ponsole-Lenfant, H. Gara, P. Roll, C. Leveque, A. Massacrier, G. Ferracci, J. Cillario, A. Robaglia-Schlupp, R. Vincentelli, et al. (2008)
Hum. Mol. Genet. 17, 3617-3630
   Abstract »    Full Text »    PDF »
Cleaved Forms of the Urokinase Plasminogen Activator Receptor in Plasma Have Diagnostic Potential and Predict Postoperative Survival in Patients with Ovarian Cancer.
E. Henic, C. Borgfeldt, I. J. Christensen, B. Casslen, and G. Hoyer-Hansen (2008)
Clin. Cancer Res. 14, 5785-5793
   Abstract »    Full Text »    PDF »
Urokinase-type Plasminogen Activator Receptor Induces Conformational Changes in the Integrin {alpha}M{beta}2 Headpiece and Reorientation of Its Transmembrane Domains.
M.-L. Tang, A. Vararattanavech, and S.-M. Tan (2008)
J. Biol. Chem. 283, 25392-25403
   Abstract »    Full Text »    PDF »
The inhibitory effect of HKa in endothelial cell tube formation is mediated by disrupting the uPA-uPAR complex and inhibiting its signaling and internalization.
Y. Liu, D. J. Cao, I. M. Sainz, Y.-L. Guo, and R. W. Colman (2008)
Am J Physiol Cell Physiol 295, C257-C267
   Abstract »    Full Text »    PDF »
A Composite Role of Vitronectin and Urokinase in the Modulation of Cell Morphology upon Expression of the Urokinase Receptor.
T. Hillig, L. H. Engelholm, S. Ingvarsen, D. H. Madsen, H. Gardsvoll, J. K. Larsen, M. Ploug, K. Dano, L. Kjoller, and N. Behrendt (2008)
J. Biol. Chem. 283, 15217-15223
   Abstract »    Full Text »    PDF »
uPAR-induced cell adhesion and migration: vitronectin provides the key.
C. D. Madsen, G. M. S. Ferraris, A. Andolfo, O. Cunningham, and N. Sidenius (2007)
J. Cell Biol. 177, 927-939
   Abstract »    Full Text »    PDF »
H. Gardsvoll and M. Ploug (2007)
J. Biol. Chem. 282, 13561-13572
   Abstract »    Full Text »    PDF »
Pro-urokinase-type Plasminogen Activator Is a Substrate for Hepsin.
P. Moran, W. Li, B. Fan, R. Vij, C. Eigenbrot, and D. Kirchhofer (2006)
J. Biol. Chem. 281, 30439-30446
   Abstract »    Full Text »    PDF »
Characterization of the Functional Epitope on the Urokinase Receptor: COMPLETE ALANINE SCANNING MUTAGENESIS SUPPLEMENTED BY CHEMICAL CROSS-LINKING.
H. Gardsvoll, B. Gilquin, M. H. Le Du, A. Menez, T. J. D. Jorgensen, and M. Ploug (2006)
J. Biol. Chem. 281, 19260-19272
   Abstract »    Full Text »    PDF »
A Region in Urokinase Plasminogen Receptor Domain III Controlling a Functional Association with {alpha}5beta1 Integrin and Tumor Growth.
P. Chaurasia, J. A. Aguirre-Ghiso, O. D. Liang, H. Gardsvoll, M. Ploug, and L. Ossowski (2006)
J. Biol. Chem. 281, 14852-14863
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882