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J Biol Chem, Vol. 274, Issue 29, 20178-20184, July 16, 1999
From the Cardiovascular Research Institute, University of
California, San Francisco, California 94143-0130
The G protein-coupled thrombin receptor,
protease-activated receptor 1 (PAR1), mediates many of the actions of
thrombin on cells including chemotaxis. In contrast to the reversible
agonist binding that regulates signaling by most G protein-coupled
receptors (GPCRs), PAR1 is activated by an irreversible proteolytic
mechanism. Although activated PAR1 is phosphorylated, uncoupled, and
internalized like typical GPCRs, signal termination is additionally
dependent on lysosomal degradation of cleaved and activated receptors.
In the present study we exploit two PAR1 mutants to examine the link between chemotaxis and receptor shutoff. One, a carboxyl tail deletion
mutant (Y397Z), is defective in phosphorylation and internalization. The other, a carboxyl tail chimeric receptor (P/S), is phosphorylated and internalized upon activation but recycles to the plasma membrane like reversibly activated GPCRs. Expression of these receptors in a
hematopoietic cell line disrupted cell migration along thrombin gradients. Thrombin activation of cells expressing P/S or Y397Z resulted in persistent signaling independent of the continued presence
of thrombin. Signaling in response to the soluble agonist peptide
SFLLRN was reversible for P/S but persisted for Y397Z. Strikingly,
cells expressing P/S responded chemokinetically to thrombin but
chemotactically to SFLLRN. In contrast, Y397Z-mediated migration was
largely chemokinetic to both agonists. These studies suggest that
termination of PAR1 signaling at the level of the receptor is necessary
for gradient detection and directional migration.
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