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A Global Phosphorylation Atlas of Proteins Within Pathological Site of Rotator Cuff Tendinopathy
Yezhou Wang1, Jiawei Zhang2,3, Yuan Lin4
1School of Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
Abstract:
Rotator cuff tendinopathy (RCT) is the most common cause of shoulder pain, therefore posing an important clinical problem. Understanding the mechanism and biochemical changes of RCT would be of crucial importance and pave the path to targeting novel and effective therapeutic strategies in translational perspectives and clinical practices. Phosphorylation, as one of the most important and well-studied post-translational modifications, is tightly associated with protein activity and protein functional regulation. Here in this study, we generated a global protein phosphorylation atlas within the pathological site of human RCT patients. By using Tandem Mass Tag (TMT) labeling combined with mass spectrometry, an average of 7,741 phosphorylation sites (p-sites) and 3,026 proteins were identified. Compared with their normal counterparts, 1,668 p-sites in 706 proteins were identified as upregulated, while 73 p-sites in 57 proteins were downregulated. GO enrichment analyses have shown that majority of proteins with upregulated p-sites functioned in neutrophil-mediated immunity whereas downregulated p-sites are mainly involved in muscle development. Furthermore, pathway analysis identified NF-κB-related TNF signaling pathway and protein kinase C alpha type (PKCα)-related Wnt signaling pathway were associated with RCT pathology. At last, a weighted kinase-site phosphorylation network was built to identify potentially core kinase, from which serine/threonine-protein kinase 39 (STLK3) and mammalian STE20-like protein kinase 1 (MST1) were proposed to be positively correlated with the activation of Wnt pathway.
Insights
This study maps protein phosphorylation changes in rotator cuff tendinopathy (RCT), revealing key pathways like neutrophil immunity and muscle development. It identifies potential therapeutic targets, including STLK3 and MST1 kinases, for treating shoulder pain.
Area of Science:
- Biochemistry
- Molecular Biology
- Orthopedics
Background:
- Rotator cuff tendinopathy (RCT) is a leading cause of shoulder pain, necessitating a deeper understanding of its underlying biochemical mechanisms.
- Post-translational modifications, particularly phosphorylation, play critical roles in regulating protein activity and function, making them key to understanding disease pathology.
Purpose of the Study:
- To generate a comprehensive global protein phosphorylation atlas in human RCT pathological tissues.
- To identify differentially phosphorylated proteins and associated signaling pathways involved in RCT.
- To pinpoint potential kinase targets for novel therapeutic strategies.
Main Methods:
- Utilized Tandem Mass Tag (TMT) labeling coupled with mass spectrometry to analyze protein phosphorylation.
- Performed Gene Ontology (GO) enrichment and pathway analyses to interpret proteomic data.
- Constructed a weighted kinase-site phosphorylation network to identify core kinases.
Main Results:
- Identified an average of 7,741 phosphorylation sites (p-sites) across 3,026 proteins.
- Found 1,668 upregulated p-sites (706 proteins) mainly involved in neutrophil-mediated immunity and 73 downregulated p-sites (57 proteins) in muscle development.
- Associated RCT pathology with the NF-κB-related TNF signaling pathway and PKCα-related Wnt signaling pathway.
- Highlighted STLK3 and MST1 as potential kinases positively correlated with Wnt pathway activation.
Conclusions:
- The study provides a detailed phosphorylation landscape of RCT, uncovering significant alterations in immune and muscle-related proteins.
- Identified key signaling pathways, including TNF and Wnt, implicated in RCT pathogenesis.
- Proposes STLK3 and MST1 as potential therapeutic targets for rotator cuff tendinopathy, offering translational insights for clinical practice.
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