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1.
J Biol Chem ; 300(6): 107393, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38777143

ABSTRACT

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity gene and is a known inhibitor of T cell receptor (TCR) signaling and drug target for cancer immunotherapy. However, little is known about PTPN22 posttranslational regulation. Here, we characterize a phosphorylation site at Ser325 situated C terminal to the catalytic domain of PTPN22 and its roles in altering protein function. In human T cells, Ser325 is phosphorylated by glycogen synthase kinase-3 (GSK3) following TCR stimulation, which promotes its TCR-inhibitory activity. Signaling through the major TCR-dependent pathway under PTPN22 control was enhanced by CRISPR/Cas9-mediated suppression of Ser325 phosphorylation and inhibited by mimicking it via glutamic acid substitution. Global phospho-mass spectrometry showed Ser325 phosphorylation state alters downstream transcriptional activity through enrichment of Swi3p, Rsc8p, and Moira domain binding proteins, and next-generation sequencing revealed it differentially regulates the expression of chemokines and T cell activation pathways. Moreover, in vitro kinetic data suggest the modulation of activity depends on a cellular context. Finally, we begin to address the structural and mechanistic basis for the influence of Ser325 phosphorylation on the protein's properties by deuterium exchange mass spectrometry and NMR spectroscopy. In conclusion, this study explores the function of a novel phosphorylation site of PTPN22 that is involved in complex regulation of TCR signaling and provides details that might inform the future development of allosteric modulators of PTPN22.


Subject(s)
Protein Tyrosine Phosphatase, Non-Receptor Type 22 , Receptors, Antigen, T-Cell , Signal Transduction , Humans , Phosphorylation , Receptors, Antigen, T-Cell/metabolism , Receptors, Antigen, T-Cell/immunology , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism , Gain of Function Mutation , T-Lymphocytes/metabolism , T-Lymphocytes/immunology , Jurkat Cells , HEK293 Cells
2.
Cancer Lett ; 597: 217023, 2024 Aug 10.
Article in English | MEDLINE | ID: mdl-38852701

ABSTRACT

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness genes, SOX2 and MYC, and induced apoptosis. The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.


Subject(s)
Benzamides , Janus Kinase 2 , Pyrimidines , Receptor, ErbB-2 , Receptor, trkA , Triple Negative Breast Neoplasms , Xenograft Model Antitumor Assays , Humans , Janus Kinase 2/metabolism , Janus Kinase 2/antagonists & inhibitors , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Benzamides/pharmacology , Animals , Female , Pyrimidines/pharmacology , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/genetics , Cell Line, Tumor , Receptor, trkA/metabolism , Receptor, trkA/antagonists & inhibitors , Receptor, trkA/genetics , Mice , Cell Proliferation/drug effects , Indazoles/pharmacology , Pyrazoles/pharmacology , Signal Transduction/drug effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Protein Kinase Inhibitors/pharmacology , Mice, Nude , Drug Synergism , Bridged-Ring Compounds
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