A5050077508- Protein Tyrosine Phosphatases
- Galectins and Cancer Biology
- Diabetes and associated disorders
- Cytokine Signaling Pathways and Interactions
- Immune Cell Function and Interaction
- RNA modifications and cancer
- Glycosylation and Glycoproteins Research
- T-cell and B-cell Immunology
- Systemic Lupus Erythematosus Research
- Alkaline Phosphatase Research Studies
- Adipose Tissue and Metabolism
- ATP Synthase and ATPases Research
- Peptidase Inhibition and Analysis
- Rheumatoid Arthritis Research and Therapies
- Protein Kinase Regulation and GTPase Signaling
- Monoclonal and Polyclonal Antibodies Research
- Signaling Pathways in Disease
- Chronic Lymphocytic Leukemia Research
- PI3K/AKT/mTOR signaling in cancer
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Prostate Cancer Treatment and Research
- RNA Research and Splicing
- Digestive system and related health
- Macrophage Migration Inhibitory Factor
- Wnt/β-catenin signaling in development and cancer
University of California, San Diego
2017-2024
La Jolla Institute for Immunology
2011-2021
Collins College
2021
La Jolla Alcohol Research
2018-2020
University of Southern California
2008-2012
University of Utah
2008
Albert Einstein College of Medicine
2007
Argonne National Laboratory
1959
Rheumatoid arthritis (RA) is one of the most common chronic autoimmune diseases. Despite considerable advances in clinical treatment RA, suboptimal response to therapy and discontinuation are still unresolved challenges due systemic toxicity. It crucial importance actively target deliver therapeutic agents inflamed joints order promote situ activity decrease In this study, we found that SPARC (secreted protein acidic rich cysteine) was overexpressed synovial fluid synovium RA patients as...
Abstract PTPN22 encodes a tyrosine phosphatase that inhibits Src-family kinases responsible for Ag receptor signaling in lymphocytes and is strongly linked with susceptibility to number of autoimmune diseases. As strength TCR signal critical the thymic selection regulatory T cells (Tregs), we examined effect murine deficiency on Treg development function. In thymus, numbers pre-Tregs Tregs increased inversely level PTPN22. This increase persisted periphery could play key part reduced...
Gold(I) complexes containing N-heterocyclic carbene ligands were synthesized, characterized, and along with the antiarthritic drug, auranofin, tested as inhibitors of cysteine-dependent protein tyrosine phosphatases, which are implicated in several disease states. These compounds exhibit potencies low micromolar range against enzymes vitro. At therapeutically relevant concentrations, all inhibit PTP activity Jurkat T leukemia cells some selectivity. In addition, gold-carbene phosphatase...
A gain-of-function R620W polymorphism in the PTPN22 gene, encoding lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within catalytic domain of LYP leads to reduced activity. High-resolution structural analysis revealed molecular basis this loss function. Furthermore, Q263 variant conferred protection against systemic lupus erythematosus, reinforcing proposal inhibition...
A missense C1858T single nucleotide polymorphism in the PTPN22 gene recently emerged as a major risk factor for human autoimmunity. encodes lymphoid tyrosine phosphatase (LYP), which forms complex with kinase Csk and is critical negative regulator of signaling through T cell receptor. The results LYP-R620W variation within LYP-Csk interaction motif. LYP-W620 exhibits greatly reduced gain-of-function inhibitor signaling. Here we show that LYP constitutively interacts its substrate Lck...
The intestinal epithelium has a high rate of turnover, and dysregulation pathways that regulate regeneration can lead to tumor development; however, the negative regulators oncogenic events in are not fully understood. Here we identified feedback loop between epidermal growth factor receptor (EGFR), known mediator proliferation, transient potential cation channel, subfamily V, member 1 (TRPV1), epithelial cells (IECs). We found TRPV1 was expressed by IECs intrinsically activated upon EGFR...
PTPRS-targeted FLS-directed therapy synergizes with TNF inhibition in of arthritis.
Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the
Lymphoid-specific tyrosine phosphatase (LYP), a member of the protein (PTP) family signaling enzymes, is associated with broad spectrum autoimmune diseases. Herein we describe our structure-based lead optimization efforts within 6-hydroxy-benzofuran-5-carboxylic acid series culminating in identification compound 8b, potent and selective inhibitor LYP K(i) value 110 nM more than 9-fold selectivity over large panel PTPs. The structure complex 8b was obtained by X-ray crystallography, providing...
Targeting joint-lining fibroblast-like synoviocytes reduces the severity of arthritis.
We aimed to understand the role of tyrosine phosphatase PTPN14-which in cancer cells modulates Hippo pathway by retaining YAP cytosol-in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA).Gene/protein expression levels were measured quantitative PCR and/or Western blotting. Gene knockdown RA FLS was achieved using antisense oligonucleotides. The interaction between PTPN14 and assessed immunoprecipitation. cellular localisation SMAD3 examined via...
The lymphoid tyrosine phosphatase LYP, encoded by the PTPN22 gene, is a critical regulator of signaling in T cells and recently emerged as candidate target for therapy autoimmune diseases. Here, library screening, we identified series noncompetitive inhibitors LYP that showed activity primary cells. Kinetic analysis confirmed binding compounds to nonmutually exclusive with respect known bidentate competitive inhibitor. mechanism action lead inhibitor compound 4e was studied combination...
The fibroblast-like synoviocytes (FLS) in the synovial intimal lining of joint are key mediators inflammation and destruction rheumatoid arthritis (RA). In RA, these cells aggressively invade extracellular matrix, producing cartilage-degrading proteases inflammatory cytokines. behavior FLS is controlled by multiple interconnected signal transduction pathways involving reversible phosphorylation proteins on tyrosine residues. However, little known about role protein phosphatases (PTPs)...
Abstract Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study SSc or fibrosis. Here, we show that phosphatase PTP4A1 highly expressed fibroblasts from patients with SSc. its close homolog PTP4A2 are critical promoters TGFβ signaling primary dermal bleomycin-induced vivo. promotes human through enhancement ERK activity, which stimulates SMAD3 expression nuclear...
The PTPN11 gene, encoding the tyrosine phosphatase SHP-2, is overexpressed in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) compared with osteoarthritis (OA) FLS and promotes RA invasiveness. Here, we explored molecular basis for overexpression role of SHP-2 pathogenesis. Using computational methods, identified a putative enhancer intron 1, which contained glucocorticoid receptor- binding (GR-binding) motif. This region displayed function 2 hypermethylation sites OA FLS....
As new and more effective treatments for Alzheimer's disease (AD) emerge, the development of efficient screening strategies in educationally racially diverse primary care settings has increased importance. A set candidate tests an independent diagnostic assessment were administered to a sample 318 patients treated at geriatric center. Fifty-six subjects met criteria dementia. Exploratory analysis led three two-stage that differed composition first stage or Rapid Dementia Screen, which is...