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Characterization of cellular responses of Ptpn6 (SHP-1) cKO in hippocampus by scRNA-seq

ABSTRACT: Ptpn6 (SHP-1) is known to impact signaling pathways in immune cells in various different ways, and in many cases, SHP1 opposes immune cell activation by nonreceptor tyrosine kinases such as Syk, Jak or ZAP70. In Alzheimer’s disease, multiple AD risk genes are expressed in microglia and related to microglial regulation and function. SHP-1 interacts with ITIM domains of multiple AD GWAS genes including Siglec-11, LILRB2, PILRA, and CD33 and SHP-1 is also known as a negative regulator of DAP12/Trem2 signaling. To understand cellular pathways of ITIM signaling and delineate benefits and liabilities of ITIM signaling inhibition, here we characterize Ptpn6 cKO (Cohort I) and Ptpn6 cKO crossed with previously characterized AD mouse model TauPS2APP (Cohort II) by single cell RNA-seq. We found that Ptpn6 deletion unleashes disease-like transcriptional changes in vivo. We also discovered distinct microglia activation states associated with protective versus exacerbative Ptpn6 genotypes. Current scRNA-seq results reveal both protective and latent degenerative potential of microglia held in check by Ptpn6.

ORGANISM(S): Mus musculus

PROVIDER: GSE312503 | GEO | 2026/03/26

REPOSITORIES: GEO

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Characterization of cellular responses of Ptpn6 (SHP-1) cKO in hippocampus by scRNA-seq

Project description:Characterization of cellular responses of Ptpn6 (SHP-1) cKO in hippocampus by scRNA-seq

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Gene expression profile in the bone marrow of Ptpn6-insufficient mice with neutrophilic dermatosis-like disease (NDLD)

Project description:A total number of 1,511 probe sets in the bone marrow showed at least two-fold changes with FDR < 0.05, of which 256 probe sets had over four-fold changes. A group of 63 genes in the bone marrow of NDLD mice had more than a 4-fold change with FDR < 0.0001. From 503 genes encoding proteins with ITIM motif that binds to Ptpn6, 109 were up-regulated and 83 were down-regulated.

2015-09-30 | GSE73592 | GEO

Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation

Project description:Ptpn6 is a cytoplasmic phosphatase that functions to prevent autoimmune disease and IL-1R-dependent caspase-1-independent inflammatory disease. Conditional deletion of Ptpn6 in neutrophils (Ptpn6∆PMN) is sufficient to initiate IL-1R-dependent cutaneous inflammatory disease, but the source of IL-1 and the mechanisms behind IL-1 release remain unclear. Here, we investigated the mechanisms controlling IL-1α/β release from neutrophils by inhibiting caspase-8-dependent apoptosis and Ripk1/Ripk3/Mlkl-regulated necroptosis. Loss of Ripk1 accelerated disease onset, whereas combined deletion of caspase-8 and either Ripk3 or Mlkl strongly protected Ptpn6∆PMN mice. Ptpn6∆PMN neutrophils displayed increased p38-dependent Ripk1-independent IL-1 and TNF production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 MAP kinase activation to control TNF and IL-1α/β transcription, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3/Mlkl-dependent cell death and concomitant IL-1α/β release.

2019-11-12 | GSE139223 | GEO

Targeting PDGFRa-activated Glioblastoma through Specific Inhibition of SHP-2-mediated Signaling

Project description:SHP-2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is critical for PDGFR-driven gliomagenesis. SHP099, a novel and potent SHP-2 inhibitor, preferentially attenuated the tumorigenicity of GBM and glioma stem-like cells (GSCs) compared to normal brain cells or neural progenitor cells in vitro. Delivered orally, SHP099 crosses the blood-brain barrier (BBB) and accumulates at efficacious concentrations in the brains, as determined using two different orthotopic xenograft models. SHP099 inhibited tumor growth and extended survival in activated PDGFR-signaling xenografts alone and in combination with first-line chemotherapeutic agent, temozolomide (TMZ). This study highlights SHP-2 inhibitor SHP099 potential for treatment of clinical GBM in combination with TMZ.

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SHP-1 regulates transcription of PCK1 to control gluconeogenesis

Project description:The protein-tyrosine phosphatase SHP-1 (PTPN6) is an important glucose homeostasis modulator. Besides negatively regulating insulin signaling, the specific role of SHP-1 in metabolic control remains poorly understood. We show that SHP-1 acts as a co-activator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene, thereby modulating basal gluconeogenesis in hepatocytes. SHP-1 interacts with RNA polymerase II-subunits and signal transducer and activator of transcription 5 (STAT5), and localizes to the nucleus, where a sub-fraction of SHP-1 associates with chromatin. While SHP-1 binds to the PCK1-promoter, its loss affects RNA polymerase II-recruitment to this and other promoters of genes enriched for glucose metabolism-related functions. SHP-1-downregulation, and similarly STAT5 pharmacological inhibition reduce PCK1-transcript levels correlating with blunted gluconeogenesis. Overall, we identified a novel molecular SHP-1-function, that of a regulator of PCK1-transcription and subsequently hepatic gluconeogenesis, through physical interaction with the transcription machinery, mediated by an Akt-independent mechanism, but independent of STAT5 tyrosine-phosphorylation status.

2023-09-08 | GSE174142 | GEO

Role and function of Ptpn6 in BCR-ABL1 driven pre-B cells

Project description:In order to investigate the function of Ptpn6 in ALL, we isolated bone marrow cells from Ptpn6 +/fl mice and transformed them with BCR-ABL1. In a second transduction the BCR-ABL1 driven pre-B cells were transformed either with CRE-ERT2 or ERT2 (PMIP) and after 2 days of treatment with 4OH-Tamoxifen (0.5 micromolar) subjected to gene expression analysis.

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Transcriptomic analysis revealed an important role of PPARα signaling in SHP-1 insufficiency leading to the development of renal ischemia-reperfusion injury

Project description:In this study, we systematically analyzed differences in the expression profiles of three SHP-1 (encoded by Ptpn6)-insufficient mice and three wild-type mice after renal ischemia-reperfusion injury by RNA-sequencing.

2022-04-16 | GSE200717 | GEO

Bone marrow derived macrophage response to CSF1R stimulation or starvation after deletion of Ptpn6 or Rraga

Project description:A genome-wide CRISPR screen in primary mouse bone marrow derived macrophages identified Rraga and Ptpn6 as important regulators of cell death upon CSF-1 starvation. To explore how Rraga and Ptpn6 deletion influence cellular state after CSF-1 stimulation or during growth factor starvation, CRISPR-edited BMDMs were harvested at different timepoints after addition of CSF-1, which is required to maintain cellular survival in these cultures. RNA-seq and differential expression analyses were conducted to illuminate differential pro-survival mechanisms in cultures lacking Ptpn6 or Rraga, respectively.

2026-03-26 | GSE312715 | GEO

Role and function of Ptpn6 in BCR-ABL1 driven pre-B cells

2013-06-03 | E-GEOD-34831 | biostudies-arrayexpress

Deficiency in hematopoietic phosphatase Ptpn6/Shp1 hyperactivates the innate immune system and impairs control of bacterial infections in zebrafish embryos

Project description:Deficiency in the protein-tyrosine phosphatase SHP1/PTPN6 is linked with hematological malignancies and chronic inflammatory diseases. Here we exploited the embryonic and larval stages of zebrafish as an animal model to study ptpn6 function in the sole context of innate immunity. We show that ptpn6 knockdown induces a spontaneous inflammation-associated phenotype at the late larval stage, which was microbe-independent and enhanced instead of suppressed by glucocorticoids. When challenged with Salmonella typhimurium or Mycobacterium marinum at earlier stages of development, the innate immune system was hyperactivated to a contra-productive level that impaired the control of these pathogenic bacteria. These results demonstrate the crucial regulatory function of ptpn6 in preventing host-detrimental effects of inflammation by imposing a tight control over the level of innate immune response activation.

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