Abstract
Although dual-specificity phosphatase 5 (DUSP5), which inactivates extracellular signal-regulated kinase (ERK), suppresses tumors in several types of cancer, its functional roles remain largely unknown. Here, we show that DUSP5 is induced during lipopolysaccharide (LPS)-mediated inflammation and inhibits nuclear factor-κB (NF-κB) activity. DUSP5 mRNA and protein expression increased transiently in LPS-stimulated RAW 264.7 cells and then returned to basal levels. DUSP5 overexpression in RAW 264.7 cells suppressed the production of pro-inflammatory tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), whereas knockdown of DUSP5 increased their expression. Investigation of two major inflammatory signaling pathways, mitogen-activated protein kinase (MAPK) and NF-κB, using activator protein-1 (AP-1) and NF-κB reporter plasmids, respectively, showed that NF-κB transcription activity was downregulated by DUSP5 in a phosphatase activity-independent manner whereas AP-1 activity was inhibited by DUSP5 phosphatase activity towards ERK,. Further investigation showed that DUSP5 directly interacts with transforming growth factor beta-activated kinase 1 (TAK1) and inhibitor of κB (IκB) kinases (IKKs) but not with IκBα. DUSP5 binding to IKKs interfered with the association of TAK1 with IKKs, suggesting that DUSP5 might act as a competitive inhibitor of TAK1-IKKs association. Therefore, we propose that DUSP5 negatively regulates ERK and NF-κB in a phosphatase activity-dependent and -independent manner, respectively.
Highlights
Phosphorylation of serine, threonine, or tyrosine residues in proteins is a typical post-translational modification in eukaryotes that is a critical part of signal transduction pathways involved in important cellular processes such as cell differentiation, proliferation, apoptosis, gene expression, cytoskeletal function, and immunological signaling[1]
When Dual-specificity phosphatase 5 (DUSP5) protein expression levels were analyzed by immunoblotting using an antiDUSP5 antibody, the protein expression pattern corresponded to the mRNA expression pattern, it was Protein expression levels were quantified by scanning the immunoblots and analyzing the scans with LabWorks software
DUSP5 is a potent pro-inflammatory regulator induced by IL-2, IL-7, and IL-15, and inhibits IL-2-induced ERK1/2 activation[33,34]
Summary
Phosphorylation of serine, threonine, or tyrosine residues in proteins is a typical post-translational modification in eukaryotes that is a critical part of signal transduction pathways involved in important cellular processes such as cell differentiation, proliferation, apoptosis, gene expression, cytoskeletal function, and immunological signaling[1]. Through inactivation of the c-Jun N-terminal kinase (JNK) and p38 pathways, mitogen-activated protein kinase phosphatase-1 (MKP-1), a PTP, negatively regulates pro-inflammatory cytokines in LPS-stimulated RAW 264.7 cells[13]. Our previous studies have shown that other PTPs, including receptor-type tyrosine-protein phosphatase epsilon (PTPRE), MKP-8, PTP non-receptor type 3 (PTPN3), and PTPN7, are involved in anti-inflammatory responses. Their mRNA and protein levels are influenced by LPS treatment and changes in their expression levels reduce TNF-α levels by targeting particular MAPKs such as JNK, p38, or extracellular signal-regulated kinase (ERK) in RAW 264.7 cells[14,15,16,17]. DUSP5 is a direct transcriptional target of the tumor suppressor p53 and has tumor-suppressive functions in several types of cancer[23,24]
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