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Regulation of protease‐activated receptor‐4 signaling and trafficking
Author(s) -
Smith Thomas Horace,
Trejo JoAnn
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.664.3
Subject(s) - clathrin , endosome , microbiology and biotechnology , internalization , signal transducing adaptor protein , thrombin , g protein coupled receptor , receptor , signal transduction , protease activated receptor , endocytosis , cell signaling , biology , chemistry , biochemistry , immunology , platelet , intracellular
Protease‐activated receptors (PARs) are G‐protein coupled receptors (GPCRs) that elicit cellular responses to thrombin. PARs play pivotal roles in hemostasis, thrombosis, and inflammatory responses to tissue injury. PAR activation is unique compared to other GPCRs. Thrombin cleaves the receptor's N‐terminus to reveal a “tethered ligand” that binds in cis to the receptor, resulting in G‐protein signaling. Due to the irreversible nature of PAR activation, tight regulatory mechanisms are required to govern their signaling. Thrombin signals predominantly through the activation of PAR1 and PAR4. Most cell types express more than one PAR. Thus, delineating the mechanisms of PAR4 signal regulation is essential to understanding the regulation of thrombin signaling. The goal of this study is to define the mechanisms of PAR4 internalization. To identify the mechanism of PAR4 internalization we depleted cells of certain adaptor proteins by siRNA, which revealed that the clathrin adaptor protein complex‐2 (AP‐2) plays a necessary role in this process. Immunofluorescence microscopy experiments revealed that activated PAR4 colocalizes with clathrin and is trafficked through early endosomes, and late endosomes/lysosomes. This study highlighted several other key aspects of PAR4's signal regulation that will be presented. Supported by NIH R01 HL073328.