Interaction between RGS7 and polycystin

Kim, Emily; Arnould, Thierry; Sellin, Lorenz; Benzing, Thomas; Comella, Natalia; Kocher, Olivier; Tsiokas, Leonidas; Sukhatme, Vikas P.; Walz, Gerd

doi:10.1073/pnas.96.11.6371

Cited by 154 publications

(97 citation statements)

References 49 publications

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“…After resolving mouse cerebral cortex, hypothalamus, and PAG by SDS-PAGE, the antibodies directed to R7 proteins recognized bands of about 55 kDa for RGS7 (Kim et al, 1999;Posner et al, 1999), 75 kDa for RGS9-2 (Granneman et al, 1998;Rahman et al, 1999;, and 50 kDa for RGS11 (Snow et al, 1998). The vehicle, ODN-RD, or ODN-RGS#M administration brought about no significant variations on the immunoreactivity associated to R7 proteins observed in saline-treated mice.…”

Section: Resultsmentioning

confidence: 98%

The R7 Subfamily of RGS Proteins Assists Tachyphylaxis and Acute Tolerance at μ-Opioid Receptors

Garzón

López-Fando

Sánchez‐Blázquez

2003

Neuropsychopharmacol

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Section: Resultsmentioning

confidence: 98%

The R7 Subfamily of RGS Proteins Assists Tachyphylaxis and Acute Tolerance at μ-Opioid Receptors

Garzón

López-Fando

Sánchez‐Blázquez

2003

Neuropsychopharmacol

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“…There is clear precedence that distinct components of the G proteincoupled receptor (GPCR) signaling pathway, including GPCRs, ␤-arrestin, and RGS7 (regulator of G protein signaling), are regulated by ubiquitylation (31,32), thus potentially altering the duration of the GPCR-dependent response. One hypothesis generated from the present study is that regulated ␤␥ degradation (in response to agonist stimulation) may contribute to the attenuation of cellular signaling events, at the level of the G protein, by removal of an activated ␤␥ dimer.…”

Section: Discussionmentioning

confidence: 99%

γ ₂ subunit of G protein heterotrimer is an N-end rule ubiquitylation substrate

Hamilton

Cook²,

McRackan³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Heterotrimeric G proteins transduce signals from activated transmembrane G protein-coupled receptors to appropriate downstream effectors within cells. Signaling specificity is achieved in part by the specific ␣, ␤, and ␥ subunits that compose a given heterotrimer. Additional structural and functional diversity in these subunits is generated at the level of posttranslational modification, offering alternate regulatory mechanisms for G protein signaling. Presented here is the identification of a variant of the ␥ 2 subunit of G protein heterotrimer purified from bovine brain and the demonstration that this RDTASIA ␥2 variant, containing unique amino acid sequence at its N terminus, is a substrate for ubiquitylation and degradation via the N-end rule pathway. Although N-end-dependent degradation has been shown to have important functions in peptide import, chromosome segregation, angiogenesis, and cardiovascular development, the identification of cellular substrates in mammalian systems has remained elusive. The isolation of RDTASIA ␥2 from a native tissue represents identification of a mammalian N-end rule substrate from a physiological source, and elucidates a mechanism for the targeting of G protein ␥ subunits for ubiquitylation and degradation.T he G protein heterotrimer, composed of an ␣, ␤, and ␥ subunit, is complexed with the nucleotide GDP in its inactive state. Upon activation, GDP is exchanged for GTP, resulting in subunit dissociation, and the GTP-bound ␣ or the ␤␥ dimer can both subsequently modulate the activity of a variety of downstream effectors (1, 2). The ␥ subunit, although generally associated in the cell with a ␤ subunit, is the smallest and most variable heterotrimeric G protein subunit (3, 4) and has been the least well understood with regard to its specific biological function. Several well established lipid modifications of ␥ subunits include farnesylation or geranylgeranylation of the C terminus (5, 6), and these modifications play an important role in membrane association, receptor coupling, and effector regulation (7-9). Recent work suggests a role for the ␥ subunit of transducin in ubiquitylation and destabilization of G t ␤␥ dimers (10). Although it is unclear whether such observations can be extended to other distinct ␥ isoforms, the crucial question of how a ␥ subunit could be targeted to the ubiquitylation machinery in a regulated fashion also remains unanswered. The amino terminal region of ␥ subunits is the region most divergent between the 12 known ␥ isoforms (11), an observation which suggests that the first 20 amino acids may be crucial for a specific function or subcellular localization. Indeed, presented here is the identification of an N-terminal variant of the G␥ 2 subunit isolated from bovine brain. Our discovery that this RDTASIA ␥ 2 variant undergoes N-end rule degradation highlights regulated degradation as an important function for the ␥ subunit of the G protein heterotrimer, offering a mechanism by which G protein subunits can be targeted to enzymatic components of the...

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“…We then investigated whether pheromone-dependent Sst2 degradation results from ubiquitination, a modification that has been reported for some mammalian RGS proteins (32,33). Ubiquitination is the formation of an isopeptide bond between the ubiquitin polypeptide and Lys side chains of the target protein (34).…”

Section: Fig 6 Modeling Sst2 Inhibitionmentioning

confidence: 99%

Regulators of G Protein Signaling and Transient Activation of Signaling

Hao

Yıldırım

Wang

et al. 2003

Journal of Biological Chemistry

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Cellular responses to hormones and neurotransmitters are necessarily transient. The mating pheromone signal in yeast is typical. Signal initiation requires cell surface receptors, a G protein heterotrimer, and downstream effectors. Signal inactivation requires Sst2, a regulator of G protein signaling (RGS) protein that accelerates GTPase activity. We conducted a quantitative analysis of RGS and G protein expression and devised computational models that describe their activity in vivo. These results indicated that pheromone-dependent transcriptional induction of the RGS protein constitutes a negative feedback loop that leads to desensitization. Modeling also suggested the presence of a positive feedback loop leading to resensitization of the pathway. In confirmation of the model, we found that the RGS protein is ubiquitinated and degraded in response to pheromone stimulation. We identified and quantitated these positive and negative feedback loops, which account for the transient response to external signals observed in vivo.One measure of our understanding of biological systems is our ability to predict their behavior in detail. One aspect of this endeavor is to model signal transduction events, defined here as the dynamic changes that occur within a cell in response to an external stimulus (1-3). Such models can help us to understand how small changes outside a cell produce strongly amplified changes within a cell, how graded signals are converted to all-or-none responses (4), or how activators of one pathway influence the function of a second pathway (5). A second goal, and the focus of this work, is to understand how transient external signals are prevented from being propagated indefinitely within the cell. Here we describe the molecular basis for signal activation, desensitization, and eventual resensitization of G proteins by receptors and RGS 1 proteins. The experimentally observed behavior is described mechanistically by computational modeling of the pathway.For these studies we investigated the mating pheromone signaling pathway in yeast Saccharomyces cerevisiae. The yeast mating response is arguably the best characterized signal transduction pathway of any eukaryote, and it has long served as a prototype for hormone, neurotransmitter, and sensory response systems in humans (6). Disruption or activation of pathway components leads to highly specific changes that can be easily quantified. Finally, because it is a unicellular eukaryote, every cell in a population is genetically and phenotypically identical (all cells are "typical").Mating in yeast is the fusion of a and ␣ haploid cell types to form an a/␣ diploid. The events leading to fusion are initiated by specific pheromones: ␣-type cells secrete ␣-factor pheromone, which binds to a specific receptor (Ste2) on a-cells, while a-cells secrete a-factor that binds to receptors (Ste3) on ␣-cells. Upon pheromone binding to its receptor, the G protein ␣ subunit (Gpa1) releases GDP, binds to GTP, and liberates the G protein ␤␥ subunits (Ste4/Ste18). Sustained...

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Interaction between RGS7 and polycystin

Cited by 154 publications

References 49 publications

The R7 Subfamily of RGS Proteins Assists Tachyphylaxis and Acute Tolerance at μ-Opioid Receptors

The R7 Subfamily of RGS Proteins Assists Tachyphylaxis and Acute Tolerance at μ-Opioid Receptors

γ ₂ subunit of G protein heterotrimer is an N-end rule ubiquitylation substrate

Regulators of G Protein Signaling and Transient Activation of Signaling

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Interaction between RGS7 and polycystin

Cited by 154 publications

References 49 publications

The R7 Subfamily of RGS Proteins Assists Tachyphylaxis and Acute Tolerance at μ-Opioid Receptors

The R7 Subfamily of RGS Proteins Assists Tachyphylaxis and Acute Tolerance at μ-Opioid Receptors

γ 2 subunit of G protein heterotrimer is an N-end rule ubiquitylation substrate

Regulators of G Protein Signaling and Transient Activation of Signaling

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γ ₂ subunit of G protein heterotrimer is an N-end rule ubiquitylation substrate