Protein tyrosine phosphatase epsilonC selectively inhibits interleukin-6- and interleukin- 10-induced JAK-STAT signaling.
Protein tyrosine phosphatase (PTP) epsilon (PTPepsilon) exists as 2 forms generated by alternative promoter usage. It has recently been reported that a cytosolic isoform of PTPepsilon (PTPepsilonC) when over-expressed in murine M1 myeloid cells inhibits interleukin-6 (IL-6)- and leukemia inhibitory factor-induced activation of Janus kinases (JAKs), thereby suppressing STAT3 tyrosine phosphorylation and STAT3 signaling. This study characterizes an inhibitory action of PTPepsilonC on IL-6 signaling and also reveals that PTPepsilonC inhibitory activity is independent of other potential negative regulators, such as SHP-2 and SOCS family proteins. Furthermore, it analyzes the selectivity of PTPepsilonC action toward several cytokines. On IL-6 stimulation, expression of PTPepsilonC-DA, a catalytically inactive mutant of PTPepsilonC, results in an earlier onset of STAT3 tyrosine phosphorylation, suggesting different modes of action between PTPepsilonC and other negative regulators. In addition, the study shows PTPepsilonC-DA enhances activation of STAT1 by IL-6 as well. In terms of specificity to cytokines, over-expressed PTPepsilonC also inhibits IL-10-induced tyrosine phosphorylation of STAT3 in M1 cells, whereas PTPepsilonC does not affect either interferon-beta- and interferon-gamma-induced tyrosine phosphorylation of STATs or expression of STAT transcriptional targets. Among cytokines tested, the inhibitory effect of PTPepsilonC is selective to IL-6- and IL-10-induced JAK-STAT signaling.
Tanuma
N
N
Division of Biochemical Oncology and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Shima
H
H
Nakamura
K
K
Kikuchi
K
K
D016475:3T3 Cells; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors*; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D053613:Janus Kinase 1; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011506:Proteins / Q000502:physiology; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D018123:Receptors, Interleukin / Q000187:drug effects; D053701:Receptors, Interleukin-10; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors; D014162:Transfection; D000093242:Interleukin-6 Inhibitors
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D016899:Interferon-beta; D007371:Interferon-gamma; D016753:Interleukin-10; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D053613:Janus Kinase 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053634:TYK2 Kinase; D015534:Trans-Activators; D014157:Transcription Factors; D000093242:Interleukin-6 Inhibitors; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; C490825:PTPRE protein, human; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; C098067:Ptpre protein, mouse