Shaun R.
Coughlin, M.D., Ph.D.
Director, Cardiovascular Research Institute (CVRI); Professor of Medicine and Cellular and Molecular
Pharmacology

Contact Information:
coughlin@cvrimail.ucsf.edu
Tel: (415) 476-6174
Fax: (415) 476-8173
Box 2240
Genentech Hall
Room S-472D

Links:
PIBS
UCSF Comprehensive
Cancer Center
Biomedical Sciences

Publications

Signaling by proteases and G protein-coupled receptors, and role of protease-activated receptors in vivo

Protease Signaling.
Thrombin, the effector protease for the coagulation cascade, elicits a host of cellular response. How does thrombin, a protease, behave like a hormone to activate cells? We have characterized a family of protease-activated G protein-coupled receptors (PARs) that are activated by an unusual mechanism. Thrombin cleaves PAR1's amino terminal exodomain to unmask a new amino terminus that then serves as a tethered peptide ligand, binding intramolecularly to the body of the receptor to cause transmembrane signaling. PAR1 is the prototype for a small family of PARs. PAR2 is activated by trypsin-like proteases. PAR3 and PAR4 are newly identified thrombin receptors.

Current work focuses on:
PAR activation. We are examining possible PAR-PAR interactions and novel cofactor mechanisms.

Receptor trafficking. The irreversibility of PAR1's proteolytic activation mechanism raises the question of how its signaling is terminated. We are using biochemical and somatic cell genetic approaches to identify how activated PAR1 is internalized and sorted to lysosomes.

PARs and platelets. To define the roles of PARs in vivo, we generated mice deficient in PAR1, PAR2, and PAR3; a PAR4 knockout is in progress. We are testing a model in which PAR3 and PAR4 mediate activation of mouse platelets and PAR1 and PAR4 activate human platelets.

PARs in embryonic development. Thrombin's not just for coagulation anymore? Approximately half of PAR1-deficient mouse embryos die at ~E9.5, apparently from bleeding. It appears that the "coagulation" system plays an unanticipated role in embryonic development that is unrelated to hemostasis in the usual sense. We are testing the hypothesis that the coagulation cascade functions as a "leak detector" that monitors and regulates vascular development, and that defective thrombin signaling in endothelial cells impairs blood vessel formation.

Other collaborative projects focus on the structural basis of GPCR signaling.