Protein tyrosine phosphatase εC selectively inhibits interleukin-6-and interleukin-10-induced JAK-STAT signaling

Protein tyrosine phosphatase (PTP) epsilon (PTP epsilon) exists as 2 forms generated by alternative promoter usage. It has recently been reported that a cytosolic isoform of PTP epsilon (PTP epsilonC) when over-expressed in murine M1 myeloid cells inhibits interieukin-6 (IL-6)- and leukemia inhibitory factor-induced activation of Janus kinsases (JAKs), thereby suppressing STAT3 tyrosine phosphorylation and STAT3 signaling. This study characterizes an inhibitory action of PTP epsilonC on IL-6 signaling and also reveals that PTP epsilonC Inhibitory activity is independent of other potential negative regulators, such as SHP-2 and SOCS family proteins. Furthermore, it analyzes the selectivity of PTP epsilonC action toward several cytokines. On IL-6 stimulation, expression of PTP epsilonC-DA, a catalytically inactive mutant of PTP epsilonC, results in an earlier onset of STAT3 tyrosine phosphorylation, suggesting different modes of action between PTP epsilonC and other negative regulators. In addition, the study shows PTPeC-DA enhances activation of STAT1 by IL-6 as well. In terms of specificity to cytokines, over-expressed PTP epsilonC also inhibits IL-10-induced tyrosine phosphorylation of STAT3 in M1 cells, whereas PTP epsilonC 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 PTP epsilonC is selective to IL-6-and IL-10-induced JAK-STAT signaling. (C) 2001 by The American Society of Hematology.