A structural basis for differential cell signalling by PAI-1 and PAI-2 in breast cancer cells.
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.
Croucher
David R
DR
School of Biological Sciences, University of Wollongong, NSW 2522, Australia.
Saunders
Darren N
DN
Stillfried
Gillian E
GE
Ranson
Marie
M
D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D017396:Plasminogen Activator Inhibitor 2 / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011956:Receptors, Cell Surface / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000378:metabolism
C524898:PLAUR protein, human; D017395:Plasminogen Activator Inhibitor 1; D017396:Plasminogen Activator Inhibitor 2; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D055293:Receptors, Urokinase Plasminogen Activator; C036053:VLDL receptor; D014568:Urokinase-Type Plasminogen Activator
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