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PMID:21540189

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Citation

Cheng, SB, Quinn, JA, Graeber, CT and Filardo, EJ (2011) Down-modulation of the G-protein-coupled estrogen receptor, GPER, from the cell surface occurs via a trans-Golgi-proteasome pathway. J. Biol. Chem. 286:22441-55

Abstract

GPER is a G(s)-coupled seven-transmembrane receptor that has been linked to specific estrogen binding and signaling activities that are manifested by plasma membrane-associated enzymes. However, in many cell types, GPER is predominately localized to the endoplasmic reticulum (ER), and only minor amounts of receptor are detectable at the cell surface, an observation that has caused controversy regarding its role as a plasma membrane estrogen receptor. Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. Nonvisual arrestins-2/-3 do not co-localize with GPER, and expression of arrestin-2 dominant-negative mutants lacking clathrin- or β-adaptin interaction sites fails to block GPER internalization suggesting that arrestins are not involved in GPER endocytosis. Like β1AR, which recycles to the plasma membrane, GPER co-traffics with transferrin+, Rab11+ recycling endosomes. However, endocytosed GPER does not recycle to the cell surface, but instead returns to the trans-Golgi network (TGN) and does not re-enter the ER. GPER is ubiquitinated at the cell surface, exhibits a short half-life (t½;) <1 h), and is protected from degradation by the proteasome inhibitor, MG132. Disruption of the TGN by brefeldin A induces the accumulation of endocytosed GPER in Rab11+ perinuclear endosomes and prevents GPER degradation. Our results provide an explanation as to why GPER is not readily detected on the cell surface in some cell types and further suggest that TGN serves as the checkpoint for degradation of endocytosed GPER.

Links

PubMed PMC3121390 Online version:10.1074/jbc.M111.224071

Keywords

Animals; Cattle; Cell Membrane/metabolism; Clathrin/metabolism; Down-Regulation; Endocytosis; Endosomes/metabolism; HEK293 Cells; Humans; Kinetics; Mice; Proteasome Endopeptidase Complex/metabolism; Receptors, Adrenergic, beta-1/metabolism; Receptors, CXCR4/metabolism; Receptors, G-Protein-Coupled/metabolism; Recombinant Fusion Proteins/metabolism; Ubiquitin/metabolism; trans-Golgi Network/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ADRB1

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ADRB1

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CXCR4

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CXCR4

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CXCR4

located_in

GO:0005764: lysosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CXCR4

located_in

GO:0005770: late endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER1

located_in

GO:0048471: perinuclear region of cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER1

located_in

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER1

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER1

located_in

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER1

located_in

GO:0030659: cytoplasmic vesicle membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER1

located_in

GO:0005802: trans-Golgi network

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER1

located_in

GO:0055037: recycling endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER1

involved_in

GO:0071392: cellular response to estradiol stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GPER

involved_in

GO:0071392: cellular response to estradiol stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GPER

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER

part_of

GO:0005802: trans-Golgi network

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER

part_of

GO:0005783: endoplasmic reticulum

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER

part_of

GO:0048471: perinuclear region of cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER

part_of

GO:0055037: recycling endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER

part_of

GO:0030659: cytoplasmic vesicle membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GPER

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CXCR4

part_of

GO:0005764: lysosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CXCR4

part_of

GO:0005769: early endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CXCR4

part_of

GO:0005770: late endosome

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CXCR4

part_of

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CXCR4

involved_in

GO:0071345: cellular response to cytokine stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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