Dataset Information

Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-? receptor signaling.

ABSTRACT: The protein tyrosine phosphatase PTPN22(C1858T) allelic polymorphism is associated with increased susceptibility for development of systemic lupus erythematosus (SLE) and other autoimmune diseases. PTPN22 (also known as LYP) and its mouse orthologue PEP play important roles in antigen and Toll-like receptor signaling in immune cell functions. We demonstrate here that PEP also plays an important inhibitory role in interferon-? receptor (IFNAR) signaling in mice. PEP co-immunoprecipitates with components of the IFNAR signaling complex. Pep(-/-) hematopoietic progenitors demonstrate increased IFNAR signaling, increased IFN-inducible gene expression, and enhanced proliferation and activation compared to Pep(+/+) progenitors in response to IFN-?. In addition, Pep(-/-) mice treated with IFN-? display a profound defect in hematopoiesis, resulting in anemia, thrombocytopenia, and neutropenia when compared to IFN-?-treated Pep(+/+) mice. As SLE patients carrying the PTPN22(C1858T) risk variant have higher serum IFN-? activity, these data provide a molecular basis for how type I IFNs and PTPN22 may cooperate to contribute to lupus-associated cytopenias.

SUBMITTER: Holmes DA

PROVIDER: S-EPMC4493413 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling.

Holmes Derek A DA Suto Eric E Lee Wyne P WP Ou Qinglin Q Gong Qian Q Smith Hamish R C HR Caplazi Patrick P Chan Andrew C AC

The Journal of experimental medicine 20150615 7

The protein tyrosine phosphatase PTPN22(C1858T) allelic polymorphism is associated with increased susceptibility for development of systemic lupus erythematosus (SLE) and other autoimmune diseases. PTPN22 (also known as LYP) and its mouse orthologue PEP play important roles in antigen and Toll-like receptor signaling in immune cell functions. We demonstrate here that PEP also plays an important inhibitory role in interferon-α receptor (IFNAR) signaling in mice. PEP co-immunoprecipitates with com ...[more]

PMID: 26077719

Similar Datasets

Project description:NF?B signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NF?B activation has not been previously described, although FGFs have been known to antagonize TNF?-induced apoptosis.Here, we demonstrate an interaction between FGFR4 and IKK? (Inhibitor of NF?B Kinase ? subunit), an essential component in the NF?B pathway. This novel interaction was identified utilizing a yeast two-hybrid screen [1] and confirmed by coimmunoprecipitation and mass spectrometry analysis. We demonstrate tyrosine phosphorylation of IKK? in the presence of activated FGFR4, but not kinase-dead FGFR4. Following stimulation by TNF? (Tumor Necrosis Factor ?) to activate NF?B pathways, FGFR4 activation results in significant inhibition of NF?B signaling as measured by decreased nuclear NF?B localization, by reduced NF?B transcriptional activation in electophoretic mobility shift assays, and by inhibition of IKK? kinase activity towards the substrate GST-I?B? in in vitro assays. FGF19 stimulation of endogenous FGFR4 in TNF?-treated DU145 prostate cancer cells also leads to a decrease in IKK? activity, concomitant reduction in NF?B nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNF? treatment of DU145 cells, in comparison with TNF? alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NF?B signaling.These results identify a compelling link between FGFR4 signaling and the NF?B pathway, and reveal that FGFR4 activation leads to a negative effect on NF?B signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NF?B signaling will not be limited to FGFR4 alone.

Dataset Information

Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-? receptor signaling.

Publications

Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets