The evolving plasticity of coagulation protease-dependent cytoprotective signalling

Summary

Coagulation proteases control cellular homeostasis beyond haemostasis. While the role of coagulation proteases in regulating vascular healing and thrombosis is well established, the mechanism underlying the receptor-dependent regulation of cellular function remain incompletely understood. In particular, the opposing effects of the protease-activated receptor 1 (PAR-1), dependent on the activating proteases thrombin or activated protein C generated a conundrum researchers only recently have begun to decipher. The net-effect (cellular perturbation vs. cellular protection) depends on co-receptors involved, the concentration of the activating protease, the temporal context of receptor activation, and a dynamic process of receptor rearrangement upon receptor activation. The latter scenario recruits receptors to a cytoprotective signalling pathways. Recent insights into these mechanisms are summarized in this article.

Zusammenfassung

Unabhängig von der Regulation der Hämostase kontrollieren Gerinnungsproteasen die zelluläre Homöostase. Die Mechanismen, durch die Gerinnungsproteasen vaskuläre Heilungsprozesse oder Thrombose (Hämostase) regulieren, sind gut untersucht und weitgehend verstanden. Hingegen sind die Rezeptor-vermittelten Mechanismen, durch die diese Proteasen die zelluläre Homöostase kontrollieren, bisher nur unvollständig bekannt. So vermittelt der Protease-aktivierbare Rezeptor 1 (PAR-1) in Abhängigkeit der aktivierenden Protease (Thrombin oder aktiviertes Protein C) entgegengesetzte Effekte. Neue Erkenntnisse geben erstmals Einblicke in die Mechanismen, die diesen scheinbar widersprüchlichen Befunden zu Grunde liegen. Die erzielte Wirkung (Zellprotektion versus Zellaktivierung) hängt von Ko-Rezeptoren, der Konzentration der aktivierenden Protease, dem zeitlichen Kontext der Aktivierung und dynamischen Umstrukturierungen der involvierten Rezeptorkomplexe ab. Insbesondere die Restrukturierung der Rezeptoren ist mit einer Aktivierung zytoprotektiver Signalwege assoziiert. Neue Studienergebnisse, die diesen Erkenntnissen zu Grunde liegen, werden in diesem Artikel besprochen.

Keywords

Protease activated receptor - protein C - thrombin - cytoprotection - biased signalling

Schlüsselwörter

Protease-aktivierbarer Rezeptor - Protein C - Thrombin - Zellprotektion

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