Modulation of Postendocytic Sorting of G Protein-Coupled Receptors

Whistler, Jennifer L.; Enquist, Johan; Marley, Aaron; Fong, Jamie; Gladher, Fredrik; Tsuruda, Pamela R.; Murray, Stephen R.; Zastrow, Mark von

doi:10.1126/science.1073308

Cited by 295 publications

(364 citation statements)

References 37 publications

Supporting

Mentioning

342

Contrasting

Order By: Relevance

“…Therefore, JM4, JWA, and GTRAP3-18 might comprise a family of proteins that interact not only with CCR5, but also with other GPCRs or transmembrane-spannning proteins. Other GPCR-interacting proteins such as b-arrestins or members of the family of GPCR-associated sorting proteins (GASP) have been shown to bind and regulate not only one specific but several GPCR proteins [24][25][26].…”

Section: Discussionmentioning

confidence: 99%

JM4 is a four‐transmembrane protein binding to the CCR5 receptor

2005

View full text Add to dashboard Cite

The CC chemokine receptor 5 (CCR5) is a major coreceptor for human immunodeficiency virus (HIV) and CCR5 mutants lacking the carboxy (C)-terminus interfere with HIV infection. Therefore, we analysed the C-terminus of CCR5 and here describe Jena-Muenchen 4 (JM4), a novel CCR5-interacting protein. JM4 is membrane-associated, co-precipitates with CCR5, and is ubiquitously expressed. It shares about 62% sequence similarity with JWA and glutamate transporter-associated protein 3-18 (GTRAP3-18), a regulator of an amino acid transporter. JWA, like JM4, is a four-transmembrane protein, which binds to the CCR5 receptor. Furthermore, JM4, JWA, and GTRAP3-18 co-localise and heterodimerise indicating a functional relationship. JM4 co-localises with calnexin in the endoplasmic reticulum and with the mannose 6-phosphate receptor in the Golgi. JM4 and GTRAP3-18 harbor a Rab-acceptor motif, indicating a function in vesicle formation at the Golgi complex. In conclusion, we describe a CCR5-interacting protein, which is suggested to function in trafficking and membrane localisation of the receptor, possibly also other receptors or amino acid transporters.

show abstract

Section: Discussionmentioning

confidence: 99%

JM4 is a four‐transmembrane protein binding to the CCR5 receptor

2005

View full text Add to dashboard Cite

show abstract

“…On the contrary, MOR is uncapable of interacting with GASP and rapidly recycles back to the plasma membrane after activation [45]. Exchanging the cytoplasmic tail of DOR with that of MOR swapped the postendocytic sorting profiles of the receptors [44,46]. Therefore, we used these chimeric receptors (DORMT, DOR with the C-terminal tail of MOR, and MORDT, MOR with the C-terminal tail of DOR) to test whether different endocytic and postendocytic behaviors of the receptors are linked to the regulation of BACE1 and γ-secretase.…”

Section: Postendocytic Sorting Of Activated Dor Defines β-And γ-Secrementioning

confidence: 99%

“…lular trafficking. It has been reported that binding of GPCR-associated sorting protein (GASP) to the DOR cytoplasmic tail modulates lysosomal sorting of activated DOR [44]. On the contrary, MOR is uncapable of interacting with GASP and rapidly recycles back to the plasma membrane after activation [45].…”

Section: Postendocytic Sorting Of Activated Dor Defines β-And γ-Secrementioning

confidence: 99%

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

et al. 2010

View full text Add to dashboard Cite

Dysregulation of β-site APP-cleaving enzyme (BACE) and/or γ-secretase leads to anomalous production of amyloid-β peptide (Aβ) and contributes to the etiology of Alzheimer's disease (AD). Since these secretases mediate proteolytic processing of numerous proteins, little success has been achieved to treat AD by secretase inhibitors because of inevitable undesired side effects. Thus, it is of importance to unravel the regulatory mechanisms of these secretases. Here, we show that δ-opioid receptor (DOR) promotes the processing of Aβ precursor protein (APP) by BACE1 and γ-secretase, but not that of Notch, N-cadherin or APLP. Further investigation reveals that DOR forms a complex with BACE1 and γ-secretase, and activation of DOR mediates the co-endocytic sorting of the secretases/ receptor complex for APP endoproteolysis. Dysfunction of the receptor retards the endocytosis of BACE1 and γ-secretase and thus the production of Aβ. Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Aβ pathology and Aβ-dependent behavioral deficits, but does not affect the processing of Notch, N-cadherin or APLP in AD model mice. Our study not only uncovers a molecular mechanism for the formation of a DOR/secretase complex that regulates the specificity of secretase for Aβ production but also suggests that intervention of either formation or trafficking of the GPCR/secretase complex could lead to a new strategy against AD, potentially with fewer side effects.

show abstract

“…Receptor-associated proteins play important roles during receptor endocytosis and intracellular trafficking. A number of proteins that bind to the MOPr have been recently identified and functionally characterized [12][13][14][15][16]. We have previously identified and characterized a novel MOPr-interacting protein, the membrane glycoprotein M6a, which interacts with the MOPr and plays a role in receptor endocytosis in transfected human embryonic kidney 293 (HEK293) cells [17].…”

Section: Introductionmentioning

confidence: 99%

Membrane glycoprotein M6A promotes μ-opioid receptor endocytosis and facilitates receptor sorting into the recycling pathway

Liang

Stumm

et al. 2008

Cell Res

View full text Add to dashboard Cite

The interaction of μ-opioid receptor (MOPr) with the neuronal membrane glycoprotein M6a is known to facilitate MOPr endocytosis in human embryonic kidney 293 (HEK293) cells. To further study the role of M6a in the post-endocytotic sorting of MOPr, we investigated the agonist-induced co-internalization of MOPr and M6a and protein targeting after internalization in HEK293 cells that co-expressed HA-tagged MOPr and Myc-tagged M6a. We found that M6a, MOPr, and Rab 11, a marker for recycling endosomes, co-localized in endocytotic vesicles, indicating that MOPr and M6a are primarily targeted to recycling endosomes after endocytosis. Furthermore, co-expression of M6a augmented the post-endocytotic sorting of δ-opioid receptors into the recycling pathway, indicating that M6a might have a more general role in opioid receptor post-endocytotic sorting. The enhanced post-endocytotic sorting of MOPr into the recycling pathway was accompanied by a decrease in agonist-induced receptor down-regulation of M6a in co-expressing cells. We tested the physiological relevance of these findings in primary cultures of cortical neurons and found that co-expression of M6a markedly increased the translocation of MOPrs from the plasma membrane to intracellular vesicles at steady state and significantly enhanced both constitutive and agonist-induced receptor endocytosis. In conclusion, our results strongly indicate that M6a modulates MOPr endocytosis and post-endocytotic sorting and has an important role in receptor regulation.

show abstract

Modulation of Postendocytic Sorting of G Protein-Coupled Receptors

Cited by 295 publications

References 37 publications

JM4 is a four‐transmembrane protein binding to the CCR5 receptor

JM4 is a four‐transmembrane protein binding to the CCR5 receptor

A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis

Membrane glycoprotein M6A promotes μ-opioid receptor endocytosis and facilitates receptor sorting into the recycling pathway

Contact Info

Product

Resources

About