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1956 Part XII: Hemostasis and Thrombosis Chapter 114: Control of Coagulation Reactions 1957

A B Figure 114–6. Biased protease-activated receptor (PAR)-1 signal-
ing dependent on activation by thrombin or activated protein C
IIa (APC). Activation of PAR-1 by thrombin results in endothelial barrier-
disruptive signaling (A) but activation of PAR-1 by APC in caveolae
Caveolae
C av eola e that also contain endothelial cell protein C receptor (EPCR) results in
PAR-1 endothelial barrier-protective signaling (B). 252,253 The different PAR-1
signaling induced by thrombin and APC are caused by different
254
proteolysis cleavage sites in PAR-1 for thrombin and APC. Thrombin
activates PAR-1 by cleavage at Arg41 (C). Synthetic agonist peptides
with the N-terminal tethered-ligand sequence beginning with res-
PAR-1 EPCR idue 42 are known as TRAP (thrombin receptor-activating peptide)
and cause thrombin-like effects on cells. APC activates PAR-1 by
cleavage at Arg46 (C). A synthetic agonist peptide with the N-ter-
minal tethered-ligand sequence beginning with residue 47 (TR47)
RhoA Rac1 causes APC-like effects on cells. Activation of PAR-1 by thrombin or
endothelial barrier endothelial barrier TRAP induces PAR-1 conformations such that the intracellular loops
disruption protection of PAR-1 preferentially interact with G proteins (termed “G-protein
biased”) resulting in G-protein–dependent signaling whereas acti-
C Thrombin APC vation of PAR-1 by APC or TR47 induces PAR-1 conformations that
Arg41 Arg46 preferentially interact with β-arrestin-2 (termed “β-arrestin biased”)
resulting in β-arrestin-2–dependent signaling (D). 254,256 The impli-
cation of biased PAR-1 signaling are evident by the differences in
. . . L D P R S F L L R N P N D K Y . . . phosphorylation of extracellular signal-regulated kinase (ERK)1/2
TRAP compared to Akt because TRAP, but not TR47, induces phosphoryla-
TR47 tion of ERK1/2, whereas TR47 but not TRAP induces phosphorylation
D
of Akt (E). (Reproduced with permission of Griffin JH, Zlokovic BV, Mos-
254
PAR1 cleavage at Arg41 PAR1 cleavage at Arg46 nier LO: Activated protein C: Biased for translation. Blood 125(19):2898–
2907, 2015.)
TRAP Thrombin APC TR47

Agonist bias

G-protein β-arrestin
biased Balanced biased

Signaling bias Signaling bias
G-protein β-arrestin
ERK1/2 PI3K/Akt
RhoA Rac1

Proinflammatory Cytoprotective
effects effects
E TRAP 4 TRAP
pT202/Y204-ERK1/2 (fold) 5 pSer473-Akt (fold) 3
TR47
TR47
4
3
2
2

1
0 1
0
0 1 15 60 180 0 1 15 60 180
Time (min) Time (min)

Kaushansky_chapter 114_p1949-1966.indd 1957 9/18/15 10:06 AM