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Protease Activated Receptors (PARs)
Molecular Cell Biology, 2013
Paul Bauer
Jens Berndtsson
Eva Darai
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Signaling through both G-protein
pathway and β-arrestin pathway
PARs activates multiple downstream
signaling pathways through these two
general ways (e.g. MAPK, NFκB)
Coughlin. 2000, Nature
Adams et al. 2011, Pharmacology & Therapeutics
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Member of seven transmembrane
helices receptor superfamily (GPCR)
Four different types in humans,
PAR1-4
Irreversible activated/inactivated by
N-terminal peptide cleavage by
proteases
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Precise protease activity determine
receptor activity
Target sequence differs between
PAR1-4
Ossovskaya and Bunnett. 2004, Physiology Rev
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Boire et al. 2005, Cell
PARs are essential for normal development
Misregulation of signal peptide cleavage can
result in unwanted receptor activation
PAR activity has been implicated in several
diseases
Over-activation through MMP-1 cleavage
facilitates breast cancer
Adams et al. 2011, Pharmacology
& Therapeutics
GPCR and PAR 101
Wide range of proteases cleave PARs
Adams et al. 2011,
Pharmacology
& Therapeutics
Bockaert and Pin. 1999, EMBO
GPRCRs
of the largest families of proteins
in the mammalian genome
Mediate extracellular messages by interacting
with G proteins
Large variety of ligands
• PAR1: Potential cleavage
site for thrombin
• PAR2: 30% amino acid
identity to PAR1. Putative
trypsin cleavage site
• PAR3: 28% sequence
homology to human PAR1
and PAR2. Thrombin
cleavage site.
• PAR4: . 33% homologous
to the other human PARs,
Cleavage site for thrombin
and trypsin
PARs
- N-terminus cleaved by soluble proteases
- New N-terminus exposed
- Tethered ligand domain,
binds intramolecularly to induce
intracellular signal transduction
- activates the cleaved receptor
OR
- generate a disabled receptor
Receptor structure and
downstream signaling
β-arrestin pathway
PAR2 most
completely
characterized.
• Phosphorylated cterminus of PAR binds
to the scaffold protein
β-arrestin.
• Mediate downstream
signaling by also
binding other peptide,
permitting complex
formations.
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Adams et al.
2011,
Pharmacology
& Therapeutics
Adams et al. 2011, Pharmacology
& Therapeutics
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N-terminus
Signal- and pro-peptideregions
Tethered ligand
Hirudin-like domains (PAR1/3)
N-glycosylation sites
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Transmembrane region
Three extracellular loops (ECL)
Three intracellular loops (ICL)
Cystein for disulfide-link (ECL2TM3)
PTM sites
N-glycosylation sites
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G-protein pathway
PAR1/2: Gαq, Gαi, Gα12/13, Gβγ, NFκB (inflammatory response,
mostly PAR2)
PAR3: unclear, serves as co-factor for PAR4 but also seems to
have own signaling pathways activating ERK among others.
PAR4: Gαq, Gαi/o
C-terminus
Putative palmitylation sites
Tyrosin based motif for regulation of
receptor trafficking
PTM sites
Coughlin. 2000, Nature
Implications for cancer
Ossovskaya and Bunnett. 2004, Physiology Rev
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PAR receptors have been implicateted in a number of diseases
Function of PAR is important for normal development
Mis-regulation has been linked to several forms of cancer
Activation of PAR1 and PAR2 most studied
Boire et al. 2005, Cell
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Study on the different activation by Thrombin and MMP1
Epitope cleavage is specific for both proteases
Other proteases don't cleave specific
Clevage causes downstream activation through Ca²⁺ signaling
Questions and feedback