title: Initiation and maintenance of CNTF-Jak/STAT signaling in neurons is blocked by protein tyrosine phosphatase inhibitors.
abstract: Cytokines, including interferon-gamma and ciliary neurotrophic factor (CNTF), act in common through tyrosine kinase-based Jak/STAT signaling pathways. We found that activation of the Jak/STAT pathway by both interferon-gamma and CNTF in nerve cells was rapidly terminated by tyrosine phosphatase inhibitors. Exposure of human neuroblastoma cells, BE(2)-C, first to tyrosine phosphatase inhibitors (either phenylarsine oxide or PTP inhibitor-2) prevented Jak1, STAT1 and STAT3 activation elicited subsequently by either CNTF or interferon-gamma. In contrast, exposure of these cells to phosphatase inhibitors after initial stimulation by CNTF or interferon-gamma prevented the normal time-dependent decrease of total cellular phosphotyrosine-STAT levels as expected, while excluding already formed phosphotyrosine-STAT from the nucleus. Thus, treatment of nerve cells with a tyrosine phosphatase inhibitor blocked nuclear signal transduction. A similar inhibition of CNTF-Jak/STAT signaling was observed following tyrosine phosphatase inhibition in SH-SY5Y human neuroblastoma cells, HMN-1 mouse motor neuron-neuroblastoma hybrid cells, HepG2 human hepatoma cells and embryonic chick ciliary ganglion and retinal neurons. Expression of dominant-negative forms of the tyrosine phosphatases, SHP-1 and/or SHP-2, in BE(2)-C cells had no effect on CNTF activation of STAT or on the ability of phosphatase inhibitors to block signaling. Further, results from H-35 cells expressing gp130 receptor subunits lacking functional SHP-2 binding sites revealed normal cytokine activation of Jak and STAT that was inhibited by phosphatase inhibitors. These findings suggest a critical control for regulating the initiation of Jak/STAT signaling requiring tyrosine phosphatase activity.
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, 102 Farber Hall, The State University of New York at Buffalo, Buffalo, NY 14214-3000, USA.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Jiao
authors.forename: Navjot
authors.initials: N
authors.lastname: Kaur
authors.forename: Biao
authors.initials: B
authors.lastname: Lu
authors.forename: Steven A
authors.initials: SA
authors.lastname: Reeves
authors.forename: Stanley W
authors.initials: SW
authors.lastname: Halvorsen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002645:Chickens; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007371:Interferon-gamma / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D051379:Mice; D009154:Mutation; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011233:Precipitin Tests / Q000379:methods; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse