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Revisiting the biological roles of PAI2 (SERPINB2) in cancer

Abstract

Tumour expression of the urokinase plasminogen activator correlates with invasive capacity. Consequently, inhibition of this serine protease by physiological inhibitors should decrease invasion and metastasis. However, of the two main urokinase inhibitors, high tumour levels of the type 1 inhibitor actually promote tumour progression, whereas high levels of the type 2 inhibitor decrease tumour growth and metastasis. We propose that the basis of this apparently paradoxical action of two similar serine protease inhibitors lies in key structural differences controlling interactions with components of the extracellular matrix and endocytosis–signalling co-receptors.

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Figure 1: Proteolytic cascade regulating plasminogen activation at the cell surface.
Figure 2: The proposed mechanism of improved patient prognosis associated with high plasminogen activator inhibitor type 2 (PAI2) expression.
Figure 3: Structural comparison of plasminogen activator inhibitor type 1 (PAI1) and PAI2 receptor binding interfaces showing position of key receptor binding residues.

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Acknowledgements

The work from the authors' laboratories was funded by the National Health and Medical Research Council of Australia and the Cancer Institute NSW. D.R.C., M.R. and D.N.S. are Cancer Institute NSW Fellows. The authors thank D. Ginsburg (Howard Hughes Medical Institute, University of Michigan Medical Center, Michigan, USA) for helpful discussions.

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DATABASES

National Cancer Institute

bladder cancer

breast cancer

colorectal cancer

endometrial cancer

gastric cancer

head and neck cancer

lung cancer

oral cancer

ovarian cancer

pancreatic cancer

squamous cell carcinoma

National Cancer Institute Drug Dictionary

tamoxifen

Pfam

PF00079

Protein Databank

PAI1

PAI2

Simple Modular Architecture Research Tool

SM00093

FURTHER INFORMATION

M. Ranson's homepage

Movie of serpin inhibitory mechanism

Serpin structures in Protein Data Bank

Structural Medicine database of serpin mutations

Whisstock laboratory serpin page

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Croucher, D., Saunders, D., Lobov, S. et al. Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat Rev Cancer 8, 535–545 (2008). https://doi.org/10.1038/nrc2400

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