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PTK6 domain mutants modulates action in Triple-negative breast cancer

ABSTRACT: PTK6 domain mutants modulates action in Triple-negative breast cancer

PROVIDER: PRJNA658686 | ENA |

REPOSITORIES: ENA

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PTK6 domain mutants modulates action in Triple-negative breast cancer

Project description:Protein tyrosine kinase 6 (PTK6; also called Brk) is overexpressed in 86% of breast cancer patients; high PTK6 expression predicts poor outcome. We reported PTK6 induction by HIF/GR complexes in response to either cellular or host stress. However, PTK6-driven signaling events in the context of TNBC remain undefined. In a mouse model of TNBC, manipulation of PTK6 levels (i.e. via knock-out or add-back) had little effect on primary tumor volume but altered lung metastasis. To delineate the mechanisms of PTK6 downstream signaling, we created kinase-dead (KM) and kinase-intact domain structure mutants of PTK6 via in frame deletions of the N-terminal SH3 or SH2 domains. While the PTK6 kinase domain contributed to soft-agar colony formation, PTK6 kinase activity was entirely dispensable for cell migration. Specifically, TNBC models expressing a PTK6 variant lacking the SH2 domain (SH2-del PTK6) were unresponsive to growth factor-stimulated cell motility relative to SH3-del, KM or wild-type PTK6 controls. Reverse phase protein array (RPPA) revealed that while intact PTK6 mediates spheroid formation via p38 MAPK signaling, the SH2 domain of PTK6 limits this biology, and instead mediates TNBC cell motility via activation of the RhoA and/or AhR signaling pathways. Inhibition of RhoA and/or AhR blocked TNBC cell migration as well as the branching/invasive morphology of PTK6+/AhR+ primary breast tumor tissue organoids. Inhibition of RhoA also enhanced paclitaxel cytotoxicity in TNBC cells, including in a taxane-refractory TNBC model. Together, these studies reveal that the SH2-domain of PTK6 is a potent effector of advanced cancer phenotypes in TNBC and identify RhoA and AhR as novel therapeutic targets in PTK6+ breast tumors.

2020-08-31 | GSE156676 | GEO

Quantitative proteomic profiling reveals key pathways in the anti-cancer action of methoxychalcone derivatives in triple negative breast cancer

Project description:Synthetic analogues of chalcones were investigated as potential therapeutics for triple negative breast cancer. These analogues were used in quantitative proteomic experiments to determine the mechanism of action.

2018-09-13 | PXD009553 | Pride

SETDB1 activity is globally directed by H3K14 acetylation via its Triple Tudor Domain

Project description:SETDB1 activity is globally directed by H3K14 acetylation via its Triple Tudor Domain

| PRJNA1088534 | ENA

HRPK-1, a conserved KH-domain protein, modulates microRNA activity during Caenorhabditis elegans development

Project description:HRPK-1, a conserved KH-domain protein, modulates microRNA activity during Caenorhabditis elegans development

| PRJNA573615 | ENA

AtBRO1, BRO1-like domain-containing protein, modulates growth and abiotic stress responses in Arabidopsis

Project description:AtBRO1, BRO1-like domain-containing protein, modulates growth and abiotic stress responses in Arabidopsis

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The lncRNA HOTAIR Modulates DNA-Methylation in Mesenchymal Stem Cells via Triple Helix Formation

Project description:The lncRNA HOTAIR Modulates DNA-Methylation in Mesenchymal Stem Cells via Triple Helix Formation

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PTK6 regulates secretory cell production and innate immunity in a sex-dependent manner in the intestine

Project description:PTK6 regulates regeneration and repair of the intestinal epithelium. Analysis of publicly available datasets showed Ptk6 is upregulated in tuft cells upon activation of type 2 immunity. We found that disruption of Ptk6 influences gene expression involved in intestinal immune responses. Administration of succinate, which mimics infection and activates tuft cells, revealed PTK6-dependent activation of innate immune responses in male but not female mice. In contrast to wild type and Ptk6-/- female mice, Ptk6-/- male mice do not upregulate innate immunity or differentiation of secretory cell lineages following succinate treatment. Mechanistically, we found PTK6 regulates IL-25 expression and its effector functions, which are required for activation of type 2 innate immunity only in male mice. In patients with Crohn’s disease, PTK6 is upregulated in tuft cells in noninflamed regions of intestine. These data highlight roles for PTK6 in regulating sex differences in intestinal innate immunity and provide insight into the regulation of IL-25.

2024-08-01 | GSE243229 | GEO

Transcriptome analysis for comparing the overlap mis-regulated genes between impα triple and lhp1-3 mutants.

Project description:We performed transcriptomic analysis to check the overlap mis-regulated genes between impα triple and lhp1 mutants. Overall, 87.64% genes differentially expressed in lhp1-3 are also differentially expressed in impα triple. We also observed that the number of DEGs in impα triple mutants are greater than that in lhp1-3 mutants, which is expected given that IMPα 1, 2 and 3 should also be necessary for other nucleus-localized proteins.

2020-12-31 | GSE144849 | GEO

NEK2 regulates triple negative breast cancer transcriptome.

Project description:NEK2 is a mitotic kinase that is upregulated and mislocalized in the nucleus of human cancer cells. NEK2 modulates expression and activity of both transcription and splicing factors in cancer cells, nevertheless whether this kinase affects transcriptome regulation genome widely and whether this activity concurs to its oncogenic activity is still unknown. Herein, by high-throughput RNA sequencing analysis of MDA-MB-231 cells transiently silenced for NEK2 we uncover an extensive modulation of triple-negative breast cancer cell transcriptome by this kinase.

2021-12-21 | GSE140803 | GEO

mRNA-seq of Pea3 triple mutants in 30hpf Danio rerio larvae

Project description:We performed differential DGE analysis on RNA-seq data to determine the genes misregulated in triple mutant embryos (3etv) for etv4, etv5a, and etv5b transcription factors. 3etv mutants had defects in posterior mesoderm formation, somitogenesis, and body axis straightening, as well as other Fgf related phenotypes.

2022-07-15 | GSE155014 | GEO

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