Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Unique Ligand and Kinase-Independent Roles of the Insulin Receptor in Regulation of Cell Cycle, Senescence and Apoptosis

ABSTRACT: Insulin acts through the insulin receptor (IR) tyrosine kinase to exert its classical metabolic and mitogenic actions. Here, using receptors with either short or long deletion of the β-subunit or mutation of the kinase active site (K1030R), we uncover a second novel IR signaling pathway that is intracellular domain dependent, but ligand and tyrosine kinase-independent (LYK-I). These LYK-I actions of the IR are linked to changes in phosphorylation of a network of proteins involved in the regulation of extracellular matrix organization, cell cycle, ATM signaling and cellular senescence; and result in upregulation of expression of multiple extracellular matrix-related genes and proteins, down-regulation of immune/interferon-related genes and proteins, and increased sensitivity to apoptosis. Thus, in addition to classical ligand and tyrosine kinase-dependent (LYK-D) signaling, the IR regulates a second, novel ligand and tyrosine kinase-independent (LYK-I) pathway which regulates the cellular machinery involved in senescence, matrix interaction and response to extrinsic challenges.

ORGANISM(S): Mus musculus

PROVIDER: GSE206565 | GEO | 2022/11/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Unique Ligand and Kinase-Independent Roles of the Insulin Receptor in Regulation of Cell Cycle, Senescence and Apoptosis

Project description:Insulin acts through the insulin receptor (IR) tyrosine kinase to exert its classical metabolic and mitogenic actions. Here, using receptors with either short or long deletion of the β-subunit or mutation of the kinase active site (K1030R, we uncover a second novel IR signaling pathway that is intracellular domain dependent, but ligand and tyrosine kinase-independent (LYK-I). These LYK-I actions of the IR are linked to changes in phosphorylation of a network of proteins involved in the regulation of extracellular matrix organization, cell cycle, ATM signaling and cellular senescence; and result in upregulation of expression of multiple extracellular matrix-related genes and proteins, down-regulation of immune/interferon-related genes and proteins, and increased sensitivity to apoptosis. Thus, in addition to classical ligand and tyrosine kinase-dependent (LYK-D) signaling, the IR regulates a second, novel ligand and tyrosine kinase-independent (LYK-I) pathway which regulates the cellular machinery involved in senescence, matrix interaction and response to extrinsic challenges.

2023-01-02 | PXD035587 | Pride

Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice [Mouse430_2 array]

Project description:In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated ?-gal (SA-?-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, Focal adhesion kinase and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies which rely on senescence induction by inhibiting Shp2 or controlling its target gene products may be useful in blocking breast cancer. Primary mammary tumor cells from MMTV-PyMT mice were cultured as mammospheres for 10 days and then treated with specific inhibitors of Notch (DAPT), MEK1 (U0126), FAK (TAE226), or Src (PP2) for another 2 days. Mammospheres were then subjected to RNA isolation. Each group contains 3 replicates.

2015-03-06 | E-GEOD-50517 | biostudies-arrayexpress

Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice [Mouse430_2 array]

2015-03-06 | GSE50517 | GEO

Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice [Mouse430A_2 array]

2015-03-06 | GSE50516 | GEO

Proteomics result files of phosphorylation+oxidation double PTM modification

Project description:Double PTM of tyrosine oxidation and phosphorylation MaxQuant result files, used MaxQuant version and raw result files with custom insulin reseptor (IR) peptides

2022-08-10 | MSV000090106 | MassIVE

Unique human beta-cell senescence-associated secretory phenotype (SASP) reveal conserved signaling pathways and heterogeneous factors

Project description:The aging of pancreatic beta-cells may undermine their ability to compensate for insulin resistance, leading to the development of type 2 diabetes (T2D). Aging beta-cells acquire markers of cellular senescence and develop a senescence-associated secretory phenotype (SASP) that can lead to senescence and dysfunction of neighboring cells through paracrine actions, contributing to beta-cell failure. Herein, we defined the beta-cell SASP signature based on unbiased proteomic analysis of conditioned media of cells obtained from human senescent beta-cells. These experiments revealed that the beta-cell SASP is enriched for factors associated with inflammation, cellular stress response, and extracellular matrix remodeling across species.

2021-03-18 | GSE162521 | GEO

The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain

Project description:The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain

| PRJNA830461 | ENA

Shp2 Signaling Suppresses Senescence in PyMT-induced Mammary Gland Cancer in Mice [Mouse430A_2 array]

Project description:In this study, we have used techniques from cell biology, biochemistry, and genetics to investigate the role of the tyrosine phosphatase Shp2 in tumor cells of MMTV-PyMT mouse mammary glands. Genetic ablation or pharmacological inhibition of Shp2 induces senescence, as determined by the activation of senescence-associated β-gal (SA-β-gal), cyclin-dependent kinase inhibitor 1B (p27), p53, and histone 3 trimethylated lysine 9 (H3K9me3). Senescence induction leads to inhibition of self-renewal of tumor cells and blockage of tumor formation and growth. A signaling cascade was identified that acts downstream of Shp2 to counter senescence: Src, Focal adhesion kinase and Map kinase inhibit senescence by activating the expression of S-phase kinase-associated protein 2 (Skp2), Aurora kinase A (Aurka), and the Notch ligand Delta-like 1 (Dll1), which block p27 and p53. Remarkably, the expression of Shp2 and of selected target genes predicts human breast cancer outcome. We conclude that therapies which rely on senescence induction by inhibiting Shp2 or controlling its target gene products may be useful in blocking breast cancer. For Shp2 ablation, primary mammary tumor cells from MMTV-PyMT;Shp2fl/fl mice were transduced with retroviruses expressing control GFP or CreERT2-GFP, and GFP-positive cells were purified by FACS and cultured as mammospheres for 1 week. Mammospheres were then treated with 50 nM 4-OHT for 2 hours, cultured for another 5 days, and subjected to RNA isolation. For pharmacological inhibition, primary mammary tumor cells from the same mice were cultured as mammospheres for 10 days and then treated with the Shp2 inhibitor GS493 for another 2 days. Mammospheres were then subjected to RNA isolation. Each group contains 3 replicates.

2015-03-06 | E-GEOD-50516 | biostudies-arrayexpress

Identification of a novel insulin receptor-binding protein from Momordica charantia by transcriptomic, proteomic, and docking analyses

Project description:Momordica charantia (MC) is a common vegetable in tropical areas and has been used for a long time as an alternative therapy for diabetes. Although several constituents of MC have displayed the hypoglycemic effects, the hypoglycemic targets of these constituents remain to be clarified. In this study, we analyzed and elucidated the therapeutic targets contributing to the hypoglycemic effect of aqueous extract of MC seeds (MCSE) by transcriptomic analysis. The protein ingredients aimed at the hypoglycemic target were further identified by proteomic, docking, and receptor-binding assays. Our data showed that MCSE, which was rich in small-molecular weight proteins, displayed hypoglycemic effects in normal and diabetic mice by glucose tolerance assay. MCSE significantly and primarily regulated the insulin signaling pathway in muscles and adipose tissues, suggesting that MCSE might target to insulin receptor (IR), stimulate the IR-downstream pathway, and subsequently display the hypoglycemic activity. We further identified that inhibitor against trypsin (TI) of MC directly docked into IR and activated the kinase activity of IR. In conclusion, our findings suggested that MCSE regulated glucose metabolism mainly via insulin signaling pathway. Moreover, we newly identified that TI was a novel IR-binding protein of MC that triggers the insulin signaling pathway via binding to IR.

2015-07-01 | GSE39689 | GEO

Identification of a novel insulin receptor-binding protein from Momordica charantia by transcriptomic, proteomic, and docking analyses

2015-07-01 | E-GEOD-39689 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data