Proteinase-activated receptors (PARs) - focus on receptor-receptor-interactions and their physiological and pathophysiological impact.
Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR1, PAR2, PAR3 and PAR4, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression. PARs are characterized by a unique activation mechanism involving receptor cleavage by different proteinases at specific sites within the extracellular amino-terminus and the exposure of amino-terminal "tethered ligand" domains that bind to and activate the cleaved receptors. After activation, the PAR family members are able to stimulate complex intracellular signalling networks via classical G protein-mediated pathways and beta-arrestin signalling. In addition, different receptor crosstalk mechanisms critically contribute to a high diversity of PAR signal transduction and receptor-trafficking processes that result in multiple physiological effects.In this review, we summarize current information about PAR-initiated physical and functional receptor interactions and their physiological and pathological roles. We focus especially on PAR homo- and heterodimerization, transactivation of receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases (RSTKs), communication with other GPCRs, toll-like receptors and NOD-like receptors, ion channel receptors, and on PAR association with cargo receptors. In addition, we discuss the suitability of these receptor interaction mechanisms as targets for modulating PAR signalling in disease.
Frank
F
Gieseler
Hendrik
H
Ungefroren
Utz
U
Settmacher
Morley D
MD
Hollenberg
Department of General, Visceral and Vascular Surgery, Experimental Transplantation Surgery, Jena University Hospital, Drackendorfer Str, 1, D-07747, Jena, Germany. roland.kaufmann@med.uni-jena.de.
Roland
R
Kaufmann
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000378:metabolism; D010146:Pain / Q000378:metabolism; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D020239:Receptor Cross-Talk; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation; D000071557:beta-Arrestins
D019390:Arrestins; D043562:Receptors, G-Protein-Coupled; D044462:Receptors, Proteinase-Activated; D000071557:beta-Arrestins; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases