Proteinase-activated receptors (PARs) - focus on receptor-receptor-interactions and their physiological and pathophysiological impact

Cell Commun Signal. 2013 Nov 11;11:86. doi: 10.1186/1478-811X-11-86.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Arrestins / metabolism
  • Cardiovascular Diseases / metabolism
  • Humans
  • Inflammation / metabolism
  • Molecular Targeted Therapy
  • Neoplasms / metabolism
  • Pain / metabolism
  • Protein Multimerization
  • Protein Transport
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor Cross-Talk*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Proteinase-Activated / physiology*
  • Signal Transduction
  • Transcriptional Activation
  • beta-Arrestins

Substances

  • Arrestins
  • Receptors, G-Protein-Coupled
  • Receptors, Proteinase-Activated
  • beta-Arrestins
  • Receptor Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases