Biochem. J. (2007) 408
(203–210) (Printed in Great Britain)
A structural basis for differential cell signalling by PAI-1 and PAI-2 in breast cancer cells
David R. CROUCHER*1, Darren N. SAUNDERS†‡, Gillian E. STILLFRIED* and Marie RANSON*2
*School of Biological Sciences, University of Wollongong, NSW 2522, Australia, †Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia, and ‡Department of Pathology and Laboratory Medicine, University of British Columbia and Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3
PAI-1 and PAI-2 (plasminogen-activator inibitor types 1 and 2) are inhibitors of cell surface uPA (urokinase plasminogen activator). However, tumour expression of PAI-1 and PAI-2 correlates with poor compared with good patient prognosis in breast cancer respectively. This biological divergence may be related to additional functional roles of PAI-1. For example, the inhibition of uPA by PAI-1 reveals a cryptic high-affinity site within the PAI-1 moiety for the VLDLr (very-low-density-lipoprotein receptor), which sustains cell signalling events initiated by binding of uPA to its receptor. These interactions and subsequent signalling events promote proliferation of breast cancer cells. Biochemical and structural analyses show that, unlike PAI-1, the PAI-2 moiety of uPA–PAI-2 does not contain a high-affinity-binding site for VLDLr, although uPA–PAI-2 is still efficiently endocytosed via this receptor in breast cancer cells. Furthermore, global protein tyrosine phosphorylation events were not sustained by uPA–PAI-2 and cell proliferation was not affected. We thus propose a structurally based mechanism for these differences between PAI-1 and PAI-2 and suggest that PAI-2 is able to inhibit and clear uPA activity without initiating mitogenic signalling events through VLDLr.
Key words: plasminogen-activator inhibitor type 1 (PAI-1), plasminogen-activator inhibitor type 2 (PAI-2), serpin (serine protease inhibitor), urokinase plasminogen activator (uPA), very-low-density lipoprotein receptor (VLDLr).
Abbreviations used: ERK, extracellular-signal-regulated kinase; LDLR, low-density lipoprotein receptor; LRP, low-density lipoprotein receptor-related protein; PAI, plasminogen-activator inhibitor; RAP, receptor-associated protein; RCL, reactive centre loop; serpin, serine protease inhibitor; SPR, surface plasmon resonance; uPA, urokinase plasminogen activator; uPAR, urokinase plasminogen activator receptor; VLDLr, very-low-density lipoprotein receptor.
1Present address: Cancer Research Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
2To whom correspondence should be addressed (email mranson@uow.edu.au).
Received 7 June 2007/7 August 2007; accepted 14 August 2007
Published as BJ Immediate Publication 14 August 2007, doi:10.1042/BJ20070767
© The Authors Journal compilation © 2007 Biochemical Society
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