Role of the thrombin receptor's cytoplasmic tail in intracellular trafficking. Distinct determinants for agonist-triggered versus tonic internalization and intracellular localization.

Article Details

Citation

Shapiro MJ, Trejo J, Zeng D, Coughlin SR

Role of the thrombin receptor's cytoplasmic tail in intracellular trafficking. Distinct determinants for agonist-triggered versus tonic internalization and intracellular localization.

J Biol Chem. 1996 Dec 20;271(51):32874-80.

PubMed ID
8955127 [ View in PubMed
]
Abstract

The G protein-coupled thrombin receptor is activated by an irreversible proteolytic mechanism and, perhaps as a result, exhibits an unusual trafficking pattern in the cell. Naive receptors tonically cycle between the cell surface and a protected intracellular pool, whereas receptors cleaved and activated at the cell surface internalize and move to lysosomes. Toward understanding how these trafficking events are regulated, we examined a series of receptor mutants. A receptor with alanine substitutions at all potential phosphorylation sites in the cytoplasmic tail failed to display agonist-triggered internalization but, like wild type receptor, displayed robust signaling, tonic cycling, and localization to both the cell surface and an intracellular pool. A truncation mutant that lacked most of the cytoplasmic tail also signaled robustly, lacked phosphorylation, and was defective in agonist-triggered internalization. However, in contrast to the specific phosphorylation site mutant, the truncation mutant did not display tonic cycling and localized exclusively to the cell surface. An analysis of a series of truncation mutants localized residues important for receptor trafficking to a 10-amino acid stretch in its cytoplasmic tail. These data suggest that phosphorylation may trigger internalization of activated thrombin receptors but that a second phosphorylation-independent signal mediates tonic internalization of naive receptors. They further suggest that maintenance of the intracellular pool of naive thrombin receptors requires tonic receptor internalization.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Proteinase-activated receptor 1P25116Details