A PKA/PP2A AXIS DRIVES THE GROWTH OF NEUROENDOCRINE SCLC
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE126353 | GEO | 2020/02/11
REPOSITORIES: GEO
Similar Datasets
Project description:A PKA/PP2A AXIS DRIVES THE GROWTH OF NEUROENDOCRINE SCLC
| PRJNA521690 | ENA
Project description:Using unbiased kinase profiling, we identified protein kinase A (PKA) as an active kinase in small cell lung cancer (SCLC). Inhibition of PKA activity genetically, or pharmacologically by activation of the PP2A phosphatase, inhibits SCLC expansion in culture and in vivo. Conversely, GNAS (G-protein α subunit), a PKA activator that is genetically activated in a small subset of human SCLC, promotes SCLC development. Phosphoproteomic analyses identified many new PKA substrates and mechanisms of action. In particular, PKA activity is required for the propagation of SCLC cancer stem cells in transplantation studies. Broad proteomic analysis of recalcitrant cancers has the potential to uncover novel targetable signaling networks, such as the GNAS/PKA/PP2A axis in SCLC.
2020-06-17 | PXD018209 | Pride
Project description:Musante2017 - Switching behaviour of PP2A
inhibition by ARPP-16 - mutual inhibitions and PKA inhibits
MAST3
This model is described in the article:
Reciprocal regulation of
ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated
switch in protein phosphatase 2A inhibition.
Musante V, Li L, Kanyo J, Lam TT,
Colangelo CM, Cheng SK, Brody AH, Greengard P, Le Novère N,
Nairn AC.
Elife 2017 Jun; 6:
Abstract:
ARPP-16, ARPP-19, and ENSA are inhibitors of protein
phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall
kinase inhibit PP2A during mitosis. ARPP-16 is expressed in
striatal neurons where basal phosphorylation by MAST3 kinase
inhibits PP2A and regulates key components of striatal
signaling. The ARPP-16/19 proteins were discovered as
substrates for PKA, but the function of PKA phosphorylation is
unknown. We find that phosphorylation by PKA or MAST3 mutually
suppresses the ability of the other kinase to act on ARPP-16.
Phosphorylation by PKA also acts to prevent inhibition of PP2A
by ARPP-16 phosphorylated by MAST3. Moreover, PKA
phosphorylates MAST3 at multiple sites resulting in its
inhibition. Mathematical modeling highlights the role of these
three regulatory interactions to create a switch-like response
to cAMP. Together, the results suggest a complex antagonistic
interplay between the control of ARPP-16 by MAST3 and PKA that
creates a mechanism whereby cAMP mediates PP2A
disinhibition.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000644.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
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.
2017-05-08 | BIOMD0000000644 | BioModels
Project description:Protein phosphorylation plays a crucial role in propagating cellular responses to both internal and external cues. One of the most important kinases responsible for protein phosphorylation is protein kinase A (PKA). N-[2-p-bromocinnamylamino-ethyl]-5-isoquinolinesulphonamide (H89) is often used as a “PKA specific inhibitor” to study the involvement of PKA in signaling pathways. However, evidence from cell-free experiments suggested that H89 can also inhibit other kinases. In this experiment, previously-generated mouse collecting duct cell lines with and without PKA were treated with H89, followed by mass spectrometry-based phosphoproteomics to globally assess changes in phosphorylation.
2019-03-28 | PXD011167 | Pride
Project description:Musante2017 - Switching behaviour of PP2A
inhibition by ARPP-16 - mutual inhibitions and PKA inhibits MAST3
and dominant negative effect
This model is described in the article:
Reciprocal regulation of
ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated
switch in protein phosphatase 2A inhibition.
Musante V, Li L, Kanyo J, Lam TT,
Colangelo CM, Cheng SK, Brody AH, Greengard P, Le Novère N,
Nairn AC.
Elife 2017 Jun; 6:
Abstract:
ARPP-16, ARPP-19, and ENSA are inhibitors of protein
phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall
kinase inhibit PP2A during mitosis. ARPP-16 is expressed in
striatal neurons where basal phosphorylation by MAST3 kinase
inhibits PP2A and regulates key components of striatal
signaling. The ARPP-16/19 proteins were discovered as
substrates for PKA, but the function of PKA phosphorylation is
unknown. We find that phosphorylation by PKA or MAST3 mutually
suppresses the ability of the other kinase to act on ARPP-16.
Phosphorylation by PKA also acts to prevent inhibition of PP2A
by ARPP-16 phosphorylated by MAST3. Moreover, PKA
phosphorylates MAST3 at multiple sites resulting in its
inhibition. Mathematical modeling highlights the role of these
three regulatory interactions to create a switch-like response
to cAMP. Together, the results suggest a complex antagonistic
interplay between the control of ARPP-16 by MAST3 and PKA that
creates a mechanism whereby cAMP mediates PP2A
disinhibition.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000645.
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.
2017-05-08 | BIOMD0000000645 | BioModels
Project description:RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. Further, targeting of RAS- and PP2A-regulated epigenetic proteins decreased viability of KRAS-mutant human lung cancer cells. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, this work provides a resource for future studies focusing on phosphoregulation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.
2023-02-06 | GSE220590 | GEO
Project description:RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. Further, targeting of RAS- and PP2A-regulated epigenetic proteins decreased viability of KRAS-mutant human lung cancer cells. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, this work provides a resource for future studies focusing on phosphoregulation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.
2023-02-06 | GSE220592 | GEO
Project description:RAS-mediated human cell transformation requires inhibition of the tumor suppressor Protein Phosphatase 2A (PP2A). Both RAS and PP2A mediate their effects by phosphoregulation, but phosphoprotein targets and cellular processes in which RAS and PP2A activities converge in human cancers have not been systematically analyzed. Here, based on mass spectrometry phosphoproteome data we discover that phosphosites co-regulated by RAS and PP2A are enriched on proteins involved in epigenetic gene regulation. As examples, RAS and PP2A co-regulate the same phosphorylation sites on HDAC1/2, KDM1A, MTA1/2, RNF168 and TP53BP1. Mechanistically, we validate co-regulation of NuRD chromatin repressor complex by RAS and PP2A. Consistent with their known synergistic effects in cancer, RAS activation and PP2A inhibition resulted in epigenetic reporter de-repression and activation of oncogenic transcription. Notably, transcriptional de-repression by PP2A inhibition was associated with increased euchromatin and decrease in global DNA methylation. Further, targeting of RAS- and PP2A-regulated epigenetic proteins decreased viability of KRAS-mutant human lung cancer cells. Collectively the results indicate that epigenetic protein complexes involved in oncogenic gene expression constitute a significant point of convergence for RAS hyperactivity and PP2A inhibition in cancer. Further, this work provides a resource for future studies focusing on phosphoregulation as a previously unappreciated layer of regulation of epigenetic gene regulation in cancer, and in other RAS/PP2A-regulated cellular processes.
2023-02-06 | GSE220591 | GEO
Project description:The goal of the study was to compare the response to Protien Kinase A (PKA) inhibition between Saccharomyces cerevisiae and Kluyveromyces lactis. The ancestor of K. lactis did not undergo the Whole Genome Duplication (or Whole Genome Hybridization) event that S. cerevisiae experienced. We found that many paralog pairs in S. cerevisiae were differentially induced in response to PKA inhibition, and that the shared ortholog for these paralog paris in K. lactis was typically not induced. To inhibit PKA, strains containing point mutations rendering PKA sensitive to inhibition by the ATP analog 1-NM-PP1 were generated. The transcription factors Msn2/4 and Rph1/Gis1 in S. cerevisiae and their shared orthologs in K. lactis were deleted in both species to quantify and compare the effect of those transcription factors on the response to PKA inhibition in each species.
2020-12-24 | GSE163741 | GEO
Project description:Musante2017 - Switching behaviour of PP2A
inhibition by ARPP-16 - mutual inhibitions
This model is described in the article:
Reciprocal regulation of
ARPP-16 by PKA and MAST3 kinases provides a cAMP-regulated
switch in protein phosphatase 2A inhibition.
Musante V, Li L, Kanyo J, Lam TT,
Colangelo CM, Cheng SK, Brody AH, Greengard P, Le Novère N,
Nairn AC.
Elife 2017 Jun; 6:
Abstract:
ARPP-16, ARPP-19, and ENSA are inhibitors of protein
phosphatase PP2A. ARPP-19 and ENSA phosphorylated by Greatwall
kinase inhibit PP2A during mitosis. ARPP-16 is expressed in
striatal neurons where basal phosphorylation by MAST3 kinase
inhibits PP2A and regulates key components of striatal
signaling. The ARPP-16/19 proteins were discovered as
substrates for PKA, but the function of PKA phosphorylation is
unknown. We find that phosphorylation by PKA or MAST3 mutually
suppresses the ability of the other kinase to act on ARPP-16.
Phosphorylation by PKA also acts to prevent inhibition of PP2A
by ARPP-16 phosphorylated by MAST3. Moreover, PKA
phosphorylates MAST3 at multiple sites resulting in its
inhibition. Mathematical modeling highlights the role of these
three regulatory interactions to create a switch-like response
to cAMP. Together, the results suggest a complex antagonistic
interplay between the control of ARPP-16 by MAST3 and PKA that
creates a mechanism whereby cAMP mediates PP2A
disinhibition.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000643.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
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.
2017-05-08 | BIOMD0000000643 | BioModels