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Published 2 September 2003. doi:10.1083/jcb.200302124
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© The Rockefeller University Press, 0021-9525/2003/9/789 $5.00
The Journal of Cell Biology, Volume 162, Number 5, 789-794

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GPI-anchored uPAR requires Endo180 for rapid directional sensing during chemotaxis



Justin Sturge1, Dirk Wienke1, Lucy East1, Gareth E. Jones2 and Clare M. Isacke1

1 The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK
2 The Randall Centre for Molecular Mechanisms of Cell Function, GKT School of Biomedical Sciences, New Hunt's House, London SE1 1UL, UK

Address correspondence to Clare M. Isacke, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Rd., London SW3 6JB, UK. Tel.: 44-20-7153-5510. Fax: 44-20-7153-5340. email: clare.isacke{at}icr.ac.uk

Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) play an important role in cell guidance and chemotaxis during normal and pathological events. uPAR is GPI-anchored and the mechanism by which it transmits intracellular polarity cues across the plasma membrane during directional sensing has not been elucidated. The constitutively recycling endocytic receptor Endo180 forms a trimolecular complex with uPAR in the presence of uPA, hence its alternate name uPAR-associated protein. Here, we demonstrate that Endo180 is a general promoter of random cell migration and has a more specific function in cell chemotaxis up a uPA gradient. Endo180 expression was demonstrated to enhance uPA-mediated filopodia production and promote rapid activation of Cdc42 and Rac. Expression of a noninternalizing Endo180 mutant revealed that promotion of random cell migration requires receptor endocytosis, whereas the chemotactic response to uPA does not. From these studies, we conclude that Endo180 is a crucial link between uPA–uPAR and setting of the internal cellular compass.

Key Words: Cdc42; endocytosis; migration; Rac; uPA

Justin Sturge and Dirk Wienke contributed equally to this work.

The online version of this article includes supplemental material.

Abbreviations used in this paper: CTLD, C-type lectin-like domain; ERK1/2, extracellular signal–regulated kinase 1/2; FNII, fibronectin type II domain; LRP, low density lipoprotein receptor–related protein; siRNA, small interfering RNA; uPA, urokinase-type plasminogen activator; uPAR, uPA receptor.


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