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Published online
doi:10.1083/jcb.200610154
The Journal of Cell Biology, Vol. 177, No. 5, 905-916
The Rockefeller University Press, 0021-9525 $30.00
© Wolfe et al.
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Article

Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1



Breann L. Wolfe1, Adriano Marchese2, and JoAnn Trejo1

1 Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
2 Department of Pharmacology and Experimental Therapeutics, Stritch School of Medicine, Loyola University, Maywood, IL 60153

Correspondence to JoAnn Trejo: joann_trejo{at}med.unc.edu

Protease-activated receptor-1 (PAR1), a G protein–coupled receptor (GPCR) for thrombin, is irreversibly activated by proteolysis. Consequently, PAR1 trafficking is critical for the fidelity of thrombin signaling. PAR1 displays constitutive and agonist-induced internalization, which are clathrin and dynamin dependent but are independent of arrestins. The clathrin adaptor AP2 (adaptor protein complex-2) is critical for constitutive but not for activated PAR1 internalization. In this study, we show that ubiquitination negatively regulates PAR1 constitutive internalization and specifies a distinct clathrin adaptor requirement for activated receptor internalization. PAR1 is basally ubiquitinated and deubiquitinated after activation. A PAR1 lysineless mutant signaled normally but was not ubiquitinated. Constitutive internalization of ubiquitin (Ub)-deficient PAR1 was markedly increased and inhibited by the fusion of Ub to the cytoplasmic tail. Ub-deficient PAR1 constitutive internalization was AP2 dependent like the wild-type receptor. However, unlike wild-type PAR1, AP2 was required for the internalization of activated Ub-deficient receptor, suggesting that the internalization of ubiquitinated PAR1 requires different endocytic machinery. These studies reveal a novel function for ubiquitination in the regulation of GPCR internalization.

Abbreviations used in this paper: AP2, adaptor protein complex-2; ß2AR, ß2-adrenergic receptor; CHC, clathrin heavy chain; C tail, cytoplasmic tail; CXCR4, chemokine receptor 4; EEA1, early endosomal antigen-1; GPCR, G protein–coupled receptor; Hrs, hepatocyte growth factor–regulated kinase substrate; IP, inositol phosphate; PAR, protease-activated receptor; TRAP, thrombin receptor–activating peptide; Ub, ubiquitin; UBD, Ub-binding domain.


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