Neutrophils are rapidly recruited to sites of infection and are critical for pathogen clearance. Therapeutic use of primary neutrophils has been limited, as they have a short lifespan and are not amenable to genetic manipulation. Human induced pluripotent stem cells (iPSCs) can provide a robust source of neutrophils for infusion and are genetically tractable. However, current work has indicated that dampened intracellular signaling limits iPSC-derived neutrophil (iNeutrophil) cellular activation and antimicrobial response. Here, we show that protein tyrosine phosphatase 1B (PTP1B) inhibits intracellular signaling and dampens iNeutrophil effector function. Deletion of the PTP1B phosphatase increased PI3K and ERK signaling and was associated with increased F-actin polymerization, cell migration, and phagocytosis. In contrast, other effector functions like NETosis and reactive oxygen species production were reduced. PTP1B-deficient neutrophils were more responsive to Aspergillus fumigatus and displayed rapid recruitment and control of hyphal growth. Accordingly, depletion of PTP1B increased production of inflammatory factors including the neutrophil chemokine interleukin-8. Taken together, these findings suggest that PTP1B limits iNeutrophil motility and antimicrobial function.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212797 | PMC |
| http://dx.doi.org/10.1093/jleuko/qiae039 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Semisynthesis of Nocarterphenyl A and Its Analogues.
J Nat Prod
December 2024
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China.
-Terphenyl compounds are known to possess a diverse range of biological activities, making the synthesis of novel -terphenyl derivatives a significant research objective. In this study, we report the first synthesis of nocarterphenyl A (), characterized by a thiazole-fused -terphenyl framework. Furthermore, we synthesized 18 additional analogs, including the naturally occurring compound 5-methoxy-4,7-bis(4-methoxyphenyl)benzo[]thiazol-6-ol (), employing a similar synthetic approach.
View Article and Find Full Text PDFAllosteric regulation of the tyrosine phosphatase PTP1B by a protein-protein interaction.
Protein Sci
January 2025
Department of Chemistry, Columbia University, New York, New York, USA.
The rapid identification of protein-protein interactions has been significantly enabled by mass spectrometry (MS) proteomics-based methods, including affinity purification-MS, crosslinking-MS, and proximity-labeling proteomics. While these methods can reveal networks of interacting proteins, they cannot reveal how specific protein-protein interactions alter protein function or cell signaling. For instance, when two proteins interact, there can be emergent signaling processes driven purely by the individual activities of those proteins being co-localized.
View Article and Find Full Text PDFA versatile and automatic on-line screening method: Transverse diffusion of laminar flow profiles-based capillary electrophoresis for exploring PTP1B inhibitors in natural products.
J Chromatogr A
December 2024
KU Leuven - University of Leuven, Pharmaceutical Analysis, Department of Pharmaceutical and Pharmacological Sciences, O&N2, PB 923, Herestraat 49 3000 Leuven, Belgium. Electronic address:
Natural products (NPs) play an important role in drug discovery and drug development due to their diverse chemical properties and biological activities. In the present work, an on-line capillary electrophoresis (CE) method was developed and applied to screen protein tyrosine phosphatase 1B (PTP1B) inhibitors in NPs. As a generic technique, transverse diffusion of laminar flow profiles (TDLFP) was utilized to mix all reactants in the capillary for on-line enzymatic reaction.
View Article and Find Full Text PDFKAHA ligation as a platform for the rapid discovery of Protein Tyrosine phosphatase 1B (PTP1B) inhibitors.
Bioorg Chem
December 2024
School of Pharmaceutical Science and Technology (SPST), Tianjin University, Tianjin 300072, PR China; Singapore Eye Research Institute (SERI), The Academia, 20 College Road, Discovery Tower, Singapore 169856, Singapore.
We have successfully designed and assembled a 66-member library of protein tyrosine phosphatases (PTP) inhibitor candidates using α-ketoacid-hydroxylamine (KAHA) ligation. Subsequent in situ enzymatic screening revealed a potent hit (IC = 1.67 μM) against PTP1B, which displayed 6.
View Article and Find Full Text PDFPharmacological PTP1B inhibition rescues motor learning, neuroinflammation, and hyperglycaemia in a mouse model of Alzheimer's disease.
Exp Neurol
December 2024
Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, Foresterhill, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
Background: Patients with Alzheimer's Disease (AD) frequently suffer from comorbidities such as type 2 diabetes mellitus (T2DM), accompanied by shared common pathologies such as increased inflammation and impaired glucose homeostasis. Beta-secretase 1 (BACE1), the rate limiting enzyme in AD associated beta-amyloid (Aβ) production, is also implicated in metabolic dysfunction and can increase central and peripheral protein levels of protein tyrosine phosphatase 1B (PTP1B). PTP1B is a validated target in diabetes and obesity, and is a neuroinflammatory regulator involved in degenerative processes.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!