Dataset Information

[HPP-2.0] Phosphoproteome Profiling of uEV Reveals p-AQP2 and p-GSK3β as Potential Markers for Diabetic Nephropathy

ABSTRACT: We used ultra-high-sensitivity quantitative phosphoproteomics to identify phosphoproteins in urinary extracellular vesicles (uEVs) as potential biomarkers of DN. We detected 233 phosphopeptides within the uEVs, with 47 phosphoproteins exhibiting significant alterations in patients with DN compared to those in patients with diabetes. From these phosphoproteins, we selected phosphorylated aquaporin-2 (p-AQP2[S256]) and phosphorylated glycogen synthase kinase-3β (p-GSK3β[Y216]) for validation, as they were significantly overrepresented in pathway analyses and previously implicated in DN pathogenesis.

ORGANISM(S): Homo Sapiens

SUBMITTER: Feng Zhou

PROVIDER: PXD049107 | iProX | Thu Feb 01 00:00:00 GMT 2024

REPOSITORIES: iProX

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Phosphoproteome Profiling of uEVs Reveals p-AQP2 and p-GSK3β as Potential Markers for Diabetic Nephropathy.

Li Qing Q Zhang Jiong J Fang Yi Y Dai Yan Y Jia Ping P Shen Ziyan Z Xu Sujuan S Ding Xiaoqiang X Zhou Feng F

Molecules (Basel, Switzerland) 20230724 14

Diabetic nephropathy (DN) contributes to increased morbidity and mortality among patients with diabetes and presents a considerable global health challenge. However, reliable biomarkers of DN have not yet been established. Phosphorylated proteins are crucial for disease progression. However, their diagnostic potential remains unexplored. In this study, we used ultra-high-sensitivity quantitative phosphoproteomics to identify phosphoproteins in urinary extracellular vesicles (uEVs) as potential b ...[more]

PMID: 37513479

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Project description:Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog selective inhibitors for use in acute myeloid leukemia: Genome-wide transcriptional profile for the GSK3β selective inhibitor BRD3731. Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the WNT pathway, remains a therapeutic target of interest in many diseases. While dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class to cancer therapy, particularly for the treatment of acute myeloid leukemia (AML). Knockdown of GSK3α or GSK3β individually does not increase β-catenin in certain cellular subtypes and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, only inadequate chemical tools exist. The design of selective ATP competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity, 100% similarity) in their ATP binding domains. Taking advantage of an Asp133®Glu196 “switch” in their hinge binding domains, we present a rational design strategy towards the discovery of a paralog selective set of GSK3 inhibitors. These first-in-class GSK3α and GSK3β selective inhibitors provided insights into GSK3 targeting in AML where GSK3α has been identified as a therapeutic target using genetic approaches. Our GSK3α selective compound (BRD0705) inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells while no effect is observed on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies validate feasibility of paralog selective GSK3α inhibition offering a promising therapeutic approach in AML.

Dataset Information

[HPP-2.0] Phosphoproteome Profiling of uEV Reveals p-AQP2 and p-GSK3β as Potential Markers for Diabetic Nephropathy

Publications

Phosphoproteome Profiling of uEVs Reveals p-AQP2 and p-GSK3β as Potential Markers for Diabetic Nephropathy.

Similar Datasets

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