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Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis via SYK activation

ABSTRACT: Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis via SYK activation

PROVIDER: PRJNA608435 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11165226.fastq.gz	Fastqsanger.gz
	SRR11165227.fastq.gz	Fastqsanger.gz
	SRR11165228.fastq.gz	Fastqsanger.gz
	SRR11165229.fastq.gz	Fastqsanger.gz
	SRR11165230.fastq.gz	Fastqsanger.gz

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Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis via SYK activation

Project description:Comparative transcriptome profiling reveals that wild-type and CRISPR/Cas9-engineered FES_S700C HL-60 cells have highly similar transcript levels.

2020-05-25 | GSE145811 | GEO

Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis via SYK activation

Project description:Identification of covalently bound protein targets of probe WEL028 in wild-type or mutant HL-60 cells.

2020-05-25 | PXD018270 | Pride

Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis.

Project description:Chemical tools to monitor drug-target engagement of endogenously expressed protein kinases are highly desirable for preclinical target validation in drug discovery. Here, we describe a chemical genetics strategy to selectively study target engagement of endogenous kinases. By substituting a serine residue into cysteine at the DFG-1 position in the ATP-binding pocket, we sensitize the non-receptor tyrosine kinase FES towards covalent labeling by a complementary fluorescent chemical probe. This mutation is introduced in the endogenous FES gene of HL-60 cells using CRISPR/Cas9 gene editing. Leveraging the temporal and acute control offered by our strategy, we show that FES activity is dispensable for differentiation of HL-60 cells towards macrophages. Instead, FES plays a key role in neutrophil phagocytosis via SYK kinase activation. This chemical genetics strategy holds promise as a target validation method for kinases.

| S-EPMC7316778 | biostudies-literature

SYK coordinates neuroprotective microglial responses in neurodegenerative disease [scRNA-seq]

Project description:Many neurodegenerative diseases are thought to be caused by impaired containment and/or disposal of neurotoxic material such as amyloid beta (Ab) and myelin debris. Indeed, recent human genome-wide association studies (GWAS) and animal model studies have begun to reveal critical roles for the brain’s professional phagocytes, microglia, as well as various innate immune receptors expressed by microglia in the control of neurotoxic material and subsequent neurodegenerative disease pathogenesis. Yet, the critical intracellular molecules that orchestrate the neuroprotective functions of microglia in degenerative disorders remain poorly understood. In our studies, we have identified the innate immune signaling molecule spleen tyrosine kinase (SYK) as a key regulator of microglial phagocytosis in neurodegenerative disease. We find that targeted deletion of SYK in microglia leads to exacerbated Ab deposition, aggravated neuropathology, and cognitive defects in the 5xFAD mouse model of Alzheimer’s disease (AD). Furthermore, disruption of SYK signaling in this AD model was also shown to impede the development of disease-associated microglia (DAMs), alter AKT/GSK3b-signaling in microglia, and to cause severe deficits in the ability of microglia to phagocytose Ab. Importantly, these critical neuroprotective functions of SYK in microglia were not only restricted to Ab-driven models of neurodegeneration, as we found that SYK is also a critical regulator of microglial phagocytosis and DAM phenotype acquisition in demyelinating disease. Collectively, these results help to break new ground in our understanding of the key innate immune signaling molecules that instruct beneficial microglial functions in response to neurotoxic material. Moreover, these findings suggest that targeting SYK may offer a therapeutic strategy to treat a spectrum of neurodegenerative disorders.

2022-10-15 | GSE212308 | GEO

SYK coordinates neuroprotective microglial responses in neurodegenerative disease [Bulk RNA-seq]

2022-10-15 | GSE212277 | GEO

Fes-Deficient Macrophages Prime CD8+ T Cells to Stimulate Anti-tumor Immunity and Improve Immunotherapy Efficacy

Project description:Homeostatic immunoregulatory mechanisms that prevent adverse effects of immune overaction can serve as barriers to successful anti-cancer immunity, representing attractive targets to improve cancer immunotherapy. Here, we demonstrated the role of the non-receptor tyrosine kinase Fes, abundantly expressed in immune cells, as an innate intracellular immune checkpoint. Host Fes-deficiency delayed tumor onset in a gene dose-dependent manner and improved tumor control, survival, doxorubicin efficacy, and anti-PD-1 therapy sensitization in murine triple-negative breast cancer and melanoma models. These effects were associated with a shift to an anti-tumorigenic immune microenvironment. Fes-deficient macrophages displayed increased Toll-like receptor signaling, proinflammatory cytokine production, antigen presentation to and activation of T cells, leading to increased cancer cell killing in vitro and tumor control in vivo. This study highlights Fes as an innate immune checkpoint with potential as a therapeutic target and a predictive biomarker to guide immune checkpoint inhibitor treatment.

2025-04-28 | GSE295079 | GEO

Fes

Project description:Rattus norvegicus Fes, FES proto-oncogene, tyrosine kinase [Source:RGD Symbol;Acc:1564385], is expressed in 6 baseline experiment(s);

| ENSRNOG00000011683 | ExpressionAtlas

FES

Project description:Monodelphis domestica FES, FES proto-oncogene, tyrosine kinase [Source:NCBI gene;Acc:100617717], is expressed in 2 baseline experiment(s);

| ENSMODG00000019456 | ExpressionAtlas

Fes

Project description:Rattus norvegicus Fes, FES proto-oncogene, tyrosine kinase [Source:RGD Symbol;Acc:1564385], is differentially expressed in 25 experiment(s);

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Pseudodesulfovibrio strain:SYK

Project description:Pseudodesulfovibrio sp. SYK

| PRJDB14204 | ENA