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Differential endocytosis of tissue plasminogen activator by serpins PAI-1 and PAI-2 on human peripheral blood monocytes

Journal Article


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Abstract


  • Generation of the broad spectrum protease plasmin is facilitated by the tissue (t-PA) and urokinase (u-PA) plasminogen activators, within multiple physiological and disease states. Finely tuned control of this proteolytic cascade is exerted by the plasminogen activator inhibitors type-1 (PAI-1/SERPINE1) and 2 (PAI-2/SERPINB2). Expression of this network of activators and inhibitors by cells of myeloid lineage appears to be highly interchangeable between physiological environments, and whilst the role of PAI-1 and PAI-2 in regulating u-PA-dependent functions is well established, the interaction between t-PA and PAI-2 on these cell types is poorly characterised. To this end, we used freshly isolated peripheral blood monocytes (PBM) as a model of a t-PA-dependent cellular environment. We demonstrate that while both PAI-1 and PAI-2 could inhibit surface-bound t-PA and are internalised predominately via low-density-lipoprotein receptor family members, PAI-1 enhanced the endocytosis of t-PA, whereas PAI-2 did not. Surface plasmon resonance analyses revealed differential binding affinities between the very-low-density-lipoprotein receptor and t-PA and t-PA:PAI-1 complexes in addition to those previously described with low-density-lipoprotein receptor-related protein. Moreover, t-PA:PAI-2 bound to both endocytosis receptors with similar kinetics to t-PA. These differential biochemical interactions between t-PA and the t-PA:PAI complexes may underlie the observed differences in endocytosis mechanisms on the PBMs. This suggests that while PAI-1 and PAI-2 function similarly in the control of cellular plasmin generation by t-PA, they may have disparate effects on the alternative functions of t-PA via modulation of its engagement with endocytosis receptors.

Authors


  •   Lee, Jodi (external author)
  •   Croucher, David R. (external author)
  •   Ranson, Marie

Publication Date


  • 2010

Citation


  • Lee, J. A., Croucher, D. & Ranson, M. (2010). Differential endocytosis of tissue plasminogen activator by serpins PAI-1 and PAI-2 on human peripheral blood monocytes. Thrombosis and Haemostasis, 104 (6), 1133-1142.

Scopus Eid


  • 2-s2.0-78649732417

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1668&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/629

Number Of Pages


  • 9

Start Page


  • 1133

End Page


  • 1142

Volume


  • 104

Issue


  • 6

Place Of Publication


  • http://www.thrombosis-online.com

Abstract


  • Generation of the broad spectrum protease plasmin is facilitated by the tissue (t-PA) and urokinase (u-PA) plasminogen activators, within multiple physiological and disease states. Finely tuned control of this proteolytic cascade is exerted by the plasminogen activator inhibitors type-1 (PAI-1/SERPINE1) and 2 (PAI-2/SERPINB2). Expression of this network of activators and inhibitors by cells of myeloid lineage appears to be highly interchangeable between physiological environments, and whilst the role of PAI-1 and PAI-2 in regulating u-PA-dependent functions is well established, the interaction between t-PA and PAI-2 on these cell types is poorly characterised. To this end, we used freshly isolated peripheral blood monocytes (PBM) as a model of a t-PA-dependent cellular environment. We demonstrate that while both PAI-1 and PAI-2 could inhibit surface-bound t-PA and are internalised predominately via low-density-lipoprotein receptor family members, PAI-1 enhanced the endocytosis of t-PA, whereas PAI-2 did not. Surface plasmon resonance analyses revealed differential binding affinities between the very-low-density-lipoprotein receptor and t-PA and t-PA:PAI-1 complexes in addition to those previously described with low-density-lipoprotein receptor-related protein. Moreover, t-PA:PAI-2 bound to both endocytosis receptors with similar kinetics to t-PA. These differential biochemical interactions between t-PA and the t-PA:PAI complexes may underlie the observed differences in endocytosis mechanisms on the PBMs. This suggests that while PAI-1 and PAI-2 function similarly in the control of cellular plasmin generation by t-PA, they may have disparate effects on the alternative functions of t-PA via modulation of its engagement with endocytosis receptors.

Authors


  •   Lee, Jodi (external author)
  •   Croucher, David R. (external author)
  •   Ranson, Marie

Publication Date


  • 2010

Citation


  • Lee, J. A., Croucher, D. & Ranson, M. (2010). Differential endocytosis of tissue plasminogen activator by serpins PAI-1 and PAI-2 on human peripheral blood monocytes. Thrombosis and Haemostasis, 104 (6), 1133-1142.

Scopus Eid


  • 2-s2.0-78649732417

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1668&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/629

Number Of Pages


  • 9

Start Page


  • 1133

End Page


  • 1142

Volume


  • 104

Issue


  • 6

Place Of Publication


  • http://www.thrombosis-online.com