Mechanisms regulating membrane trafficking of G protein-coupled receptors in the endocytic pathway

Zastrow, Mark von

doi:10.1016/j.lfs.2003.09.008

Cited by 151 publications

(139 citation statements)

References 38 publications

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“…Although ubiquitin functions as a signal for sorting a number of GPCRs to lysosomes, other sorting mechanisms have been described (38). In agonist-stimulated cells, the ␦ opioid receptor is rapidly degraded, whereas the opioid receptor is recycled, and exchanging their C-tails generates chimeras that, respectively, are recycled and degraded.…”

Section: Discussionmentioning

confidence: 99%

Resistance of the Human β1-Adrenergic Receptor to Agonist-induced Ubiquitination

Liang¹,

Fishman²

2004

Journal of Biological Chemistry

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Down-regulation is a classic response of most G protein-coupled receptors to prolonged agonist stimulation. We recently showed that when expressed in baby hamster kidney cells, the human ␤ 1 -but not the ␤ 2 -adrenergic receptor (AR) is totally resistant to agonistmediated down-regulation, whereas both have similar rates of basal degradation (Liang, W., Austin, S., Hoang, Q., and Fishman, P. H. (2003) J. Biol. Chem. 278, 39773-39781). To identify the underlying mechanism(s) for this resistance, we investigated the role of proteasomes, lysosomes, and ubiquitination in the degradation of ␤ 1 AR expressed in baby hamster kidney and human embryonic kidney 293 cells. Both lysosomal and proteasomal inhibitors reduced ␤ 1 AR degradation in agonist-stimulated cells but were less effective on basal degradation. To determine whether ␤ 1 AR trafficked to lysosomes we used confocal fluorescence microscopy. We observed some colocalization of ␤ 1 AR and lysosomal markers in agonist-treated cells but much less than that of ␤ 2 AR even in cells co-transfected with arrestin-2, which increases ␤ 1 AR internalization. Ubiquitination of ␤ 2 AR readily occurred in agonist-stimulated cells, whereas ubiquitination of ␤ 1 AR was not detectable even under conditions optimal for that of ␤ 2 AR. Moreover, in cells expressing ␤AR chimeras in which the C termini have been switched, the chimeric ␤ 1 AR with ␤ 2 AR C-tail underwent ubiquitination and down-regulation, but the chimeric ␤ 2 AR with ␤ 1 AR C-tail did not. Our results demonstrate for the first time that ␤ 1 AR and ␤ 2 AR differ in the ability to be ubiquitinated. Because ubiquitin serves as a signal for sorting membrane receptors to lysosomes, the lack of agonist-mediated ubiquitination of ␤ 1 AR may prevent its extensive trafficking to lysosomes and, thus, account for its resistance to down-regulation.

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Section: Discussionmentioning

confidence: 99%

Resistance of the Human β1-Adrenergic Receptor to Agonist-induced Ubiquitination

Liang¹,

Fishman²

2004

Journal of Biological Chemistry

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“…IP 3 triggers the release of Ca 2+ from the endoplasmic reticulum whereas DAG activates protein kinase C (PKC). Finally, following GPCR stimulation, the receptors undergo internalization and are sorted in the endosome for recycling or further transportation to lysosomes for degradation (von Zastrow 2003). However, in spite of a large body of growing knowledge regarding structure, signaling and trafficking of GPCRs, much remains to be known on these molecular mechanisms Yeagle & Albert, 2007).…”

Section: Structure and Signaling Pathways Of Gpcrsmentioning

confidence: 99%

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

Winzell

Åhrén

2007

Pharmacology & Therapeutics

161

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Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G-protein) coupled receptors (GPCRs). Examples of islet GPCRs are GPR40 and GPR119, which are GPCRs with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors

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“…By removing activated surface GPCRs, regulated endocytosis contributes to rapid signal termination (or desensitization), initiates new signaling pathways, and/or enables receptors to recover their signaling abilities (Sorkin and Von Zastrow, 2002;von Zastrow, 2003;Wolfe and Trejo, 2007). Ligand-induced endocytosis of GPCRs typically proceeds in several distinct steps.…”

Section: Introductionmentioning

confidence: 99%

The Ubiquitin-like Protein PLIC-2 Is a Negative Regulator of G Protein-coupled Receptor Endocytosis

N’Diaye

Hanyaloglu

Kajihara³

et al. 2008

MBoC

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The activity of many signaling receptors is regulated by their endocytosis via clathrin-coated pits (CCPs). For G protein-coupled receptors (GPCRs), recruitment of the adaptor protein arrestin to activated receptors is thought to be sufficient to drive GPCR clustering in CCPs and subsequent endocytosis. We have identified an unprecedented role for the ubiquitin-like protein PLIC-2 as a negative regulator of GPCR endocytosis. Protein Linking IAP to Cytoskeleton (PLIC)-2 overexpression delayed ligand-induced endocytosis of two GPCRs: the V2 vasopressin receptor and ␤-2 adrenergic receptor, without affecting endocytosis of the transferrin or epidermal growth factor receptor. The closely related isoform PLIC-1 did not affect receptor endocytosis. PLIC-2 specifically inhibited GPCR concentration in CCPs, without affecting membrane recruitment of arrestin-3 to activated receptors or its cellular levels. Depletion of cellular PLIC-2 accelerated GPCR endocytosis, confirming its regulatory function at endogenous levels. The ubiquitin-like domain of PLIC-2, a ligand for ubiquitin-interacting motifs (UIMs), was required for endocytic inhibition. Interestingly, the UIM-containing endocytic adaptors epidermal growth factor receptor protein substrate 15 and Epsin exhibited preferential binding to PLIC-2 over PLIC-1. This differential interaction may underlie PLIC-2 specific effect on GPCR endocytosis. Identification of a negative regulator of GPCR clustering reveals a new function of ubiquitin-like proteins and highlights a cellular requirement for exquisite regulation of receptor dynamics.

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Mechanisms regulating membrane trafficking of G protein-coupled receptors in the endocytic pathway

Cited by 151 publications

References 38 publications

Resistance of the Human β1-Adrenergic Receptor to Agonist-induced Ubiquitination

Resistance of the Human β1-Adrenergic Receptor to Agonist-induced Ubiquitination

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

The Ubiquitin-like Protein PLIC-2 Is a Negative Regulator of G Protein-coupled Receptor Endocytosis

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