PAR1-dependent biased signaling initiated by thrombin or APC. PAR1 subpopulations are localized either in membrane sections that lack caveolin-1 (A) or in caveolae that contain caveolin-1 and EPCR (B). (C) PAR1 cleavage by thrombin at Arg41 generates the N-terminal tethered-peptide agonist that begins with residue 42, whereas APC cleavage at Arg46 generates a different N-terminal tethered agonist that begins with residue 47. (D) The former cleavage results in G protein–dependent signaling, whereas the latter cleavage results in β-arrestin-2–dependent signaling. Synthetic peptides known as TRAPs that begin with amino acid 42 cause thrombinlike effects on cells, whereas a 20-mer synthetic peptide that begins with amino acid 47 (TR47) causes APC-like effects on cells .^31,34,36  (E) Such effects are illustrated by the differences in phosphorylations of ERK1/2 compared to Akt, because TRAP induces phosphorylation of ERK1/2 but not Akt, whereas TR47 induces phosphorylation of Akt but not ERK1/2.³¹  IIa, thrombin; TRAP, thrombin receptor–activating peptide.