GPR21(m5) GPR21(m5)_P6.29A GPR21(m5)_β2AR
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Jie Zheng
PROVIDER: PXD038292 | iProX | Wed Nov 23 00:00:00 GMT 2022
REPOSITORIES: iProX
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Project description:Bush2016 - Simplified Carrousel model of
GPCR
This model is described in the article:
Yeast GPCR signaling
reflects the fraction of occupied receptors, not the
number.
Bush A, Vasen G, Constantinou A,
Dunayevich P, Patop IL, Blaustein M, Colman-Lerner A.
Mol. Syst. Biol. 2016 Dec; 12(12):
898
Abstract:
According to receptor theory, the effect of a ligand depends
on the amount of agonist-receptor complex. Therefore, changes
in receptor abundance should have quantitative effects.
However, the response to pheromone in Saccharomyces cerevisiae
is robust (unaltered) to increases or reductions in the
abundance of the G-protein-coupled receptor (GPCR), Ste2,
responding instead to the fraction of occupied receptor. We
found experimentally that this robustness originates during
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model of this step, which suggested the ability to compute
fractional occupancy depends on the physical interaction
between the inhibitory regulator of G-protein signaling (RGS),
Sst2, and the receptor. Accordingly, replacing Sst2 by the
heterologous hsRGS4, incapable of interacting with the
receptor, abolished robustness. Conversely, forcing hsRGS4:Ste2
interaction restored robustness. Taken together with other
results of our work, we conclude that this GPCR pathway
computes fractional occupancy because ligand-bound GPCR-RGS
complexes stimulate signaling while unoccupied complexes
actively inhibit it. In eukaryotes, many RGSs bind to specific
GPCRs, suggesting these complexes with opposing activities also
detect fraction occupancy by a ratiometric measurement. Such
complexes operate as push-pull devices, which we have recently
described.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000637.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000637 | BioModels
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GPCR-RGS
This model is described in the article:
Yeast GPCR signaling
reflects the fraction of occupied receptors, not the
number.
Bush A, Vasen G, Constantinou A,
Dunayevich P, Patop IL, Blaustein M, Colman-Lerner A.
Mol. Syst. Biol. 2016 Dec; 12(12):
898
Abstract:
According to receptor theory, the effect of a ligand depends
on the amount of agonist-receptor complex. Therefore, changes
in receptor abundance should have quantitative effects.
However, the response to pheromone in Saccharomyces cerevisiae
is robust (unaltered) to increases or reductions in the
abundance of the G-protein-coupled receptor (GPCR), Ste2,
responding instead to the fraction of occupied receptor. We
found experimentally that this robustness originates during
G-protein activation. We developed a complete mathematical
model of this step, which suggested the ability to compute
fractional occupancy depends on the physical interaction
between the inhibitory regulator of G-protein signaling (RGS),
Sst2, and the receptor. Accordingly, replacing Sst2 by the
heterologous hsRGS4, incapable of interacting with the
receptor, abolished robustness. Conversely, forcing hsRGS4:Ste2
interaction restored robustness. Taken together with other
results of our work, we conclude that this GPCR pathway
computes fractional occupancy because ligand-bound GPCR-RGS
complexes stimulate signaling while unoccupied complexes
actively inhibit it. In eukaryotes, many RGSs bind to specific
GPCRs, suggesting these complexes with opposing activities also
detect fraction occupancy by a ratiometric measurement. Such
complexes operate as push-pull devices, which we have recently
described.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000638.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
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Project description:Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms, providing a unique opportunity to study human tumor evolution. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs compared with 5.6% (2/36) of untreated BCCs (p<0.0001), and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket (LBP) mutations that define sites of inhibitor binding and four variants that confer constitutive activity and inhibitor resistance, thus defining pivotal residues of SMO that ensure receptor autoinhibition. Finally, we show that both classes of SMO variants respond to the aPKC-ι/λ inhibitor PSI and GLI2 antagonist ATO that operate downstream of SMO
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