Age-Related Retinal Degeneration Resulting from the Deletion of Shp2 Tyrosine Phosphatase in Photoreceptor
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1122170 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29350263_1.fastq.gz | Fastqsanger.gz | |||
| SRR29350263_2.fastq.gz | Fastqsanger.gz | |||
| SRR29350264_1.fastq.gz | Fastqsanger.gz | |||
| SRR29350264_2.fastq.gz | Fastqsanger.gz | |||
| SRR29350265_1.fastq.gz | Fastqsanger.gz |
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Project description:Phosphatases play essential roles in normal cell physiology and diseases like cancer. The challenges of studying phosphatases have limited our understanding of their substrates, molecular mechanisms, and unique functions within highly complicate networks. Here we introduce a novel strategy using substrate trapping mutant coupled with quantitative mass spectrometry to identify physiological substrates of protein tyrosine phosphatase Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) in a high-throughput manner. SHP2 plays a critical role in numerous cellular processes through the regulation of various signaling pathways. The method integrates three separate MS-based experiments; in vitro dephosphorylation assay, in vivo global phosphoproteomics, and pull down of substrate trapping mutant complex using HEK293SHP2KO cells. PTPN11-C459S/D425A is an optimized substrate trap mutant of SHP2. We identified eleven direct substrates, including both known and novel SHP2 substrates in EGFR signaling pathways, among which docking protein 1 (DOK1) was further validated as a new SHP2 substrate. This advanced workflow significantly improves the systemic identification of direct substrates of phosphatase, facilitating the comprehension of equally important roles of phosphatase signaling.
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Project description:The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases (RTKs), as it is required for full RAS-ERK activation to promote cell proliferation and survival programs. SHP2 allosteric inhibitors act by stabilizing SHP2 in its auto-inhibited conformation and they are currently being tested in clinical trials for tumors with over-activation of the RAS/ERK pathway, alone and in various drug combinations. Using in vitro models, we established acquired resistant cell lines to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD-positive AML cell lines. We performed both label-free and isobaric labeling quantitative mass spectrometry-based phosphoproteomics to reveal that AML cells can restore phosphorylated ERK (pERK) in presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induces the tyrosine phosphorylation and feedback-activation of the FLT3 receptor, which in turn phosphorylates SHP2 on Tyrosine 62. This phosphorylation stabilizes SHP2 in its open conformation, preventing SHP099 binding, thus resulting in resistance. Combinatorial inhibition of SHP2 and MEK or SHP2 and FLT3 prevents pERK rebound and resistant cell growth. We observed the same mechanism in a FLT3-mutated B-ALL cell line and in the inv(16)/KITD816Y AML mouse model. Finally, we show that allosteric SHP2 inhibition does not impair the clonogenic ability of normal bone marrow progenitors, supporting its future use for clinical applications.
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Project description:Shp2, a critical SH2-domain-containing tyrosine phosphatase, is essential for cellular regulation and implicated in metabolic disruptions, obesity, diabetes, Noonan syndrome, LEOPARD syndrome, and cancers. This study focuses on Shp2 in rod photoreceptor cells, revealing its enrichment, particularly in rods. Deletion of Shp2 in rods leads to age-dependent photoreceptor degeneration. Shp2 targets occludin (OCLN), a tight junction protein, and its deletion reduces OCLN expression in the retina and retinal pigment epithelium (RPE). The isolation of actively translating mRNAs from rods lacking Shp2, followed by RNA sequencing, reveals alterations in cell cycle regulation. Additionally, altered retinal metabolism is observed in retinal cells lacking Shp2. Our studies indicate that Shp2 is crucial for maintaining the structure and function of photoreceptors.
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