title: The JAK-inhibitor, JAB/SOCS-1 selectively inhibits cytokine-induced, but not v-Src induced JAK-STAT activation.
abstract: Recently, constitutive activation of JAK kinases (JAKs) and/or signal transducers and activators of transcription (STATs) has been reported in growing numbers of human cancer cells as well as oncogene-transformed cells. JAB/SOCS-1 has been shown to be an intrinsic JAK tyrosine kinase inhibitor and to suppress the cytokine-dependent JAK-STAT pathway. In this report, we investigated the effect of ectopic expression of JAB on v-Src-induced JAK-STAT activation. Forced expression of JAB in v-Src-transformed NIH3T3 cells neither suppressed phosphorylation of STAT3 and JAK1/JAK2 nor blocked STAT3-reporter gene activation. Colony forming assay also showed that JAB did not suppress v-Src-induced transformation of NIH3T3 cells, while dominant negative STAT3 suppressed it. In contrast, JAB could downregulate phosphorylation of STAT1 and STAT3 induced by interferon gamma (IFNgamma) and interleukin-6 (IL-6) plus soluble IL6 receptor (sIL-6R), respectively. Furthermore, in vitro kinase assay indicated that JAB suppressed hyperactivation of JAK1/JAK2 and JAK1 induced by IFNgamma and IL-6 plus sIL-6R respectively, but not v-Src-induced basal JAK1/JAK2 activity. Nevertheless, both JAK1/JAK2 activated by v-Src and that activated by IL-6 plus sIL-6R could similarly bind JAB. These results clearly demonstrate that JAB distinguishes cytokine-induced JAK-STAT signaling from v-Src-induced one and can not suppress the transformation with v-Src.
authors.affiliation: Department of Ophthalmology, Nagoya University School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Iwamoto
authors.forename: T
authors.initials: T
authors.lastname: Senga
authors.forename: Y
authors.initials: Y
authors.lastname: Naito
authors.forename: S
authors.initials: S
authors.lastname: Matsuda
authors.forename: Y
authors.initials: Y
authors.lastname: Miyake
authors.forename: A
authors.initials: A
authors.lastname: Yoshimura
authors.forename: M
authors.initials: M
authors.lastname: Hamaguchi
mesh_terms: D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D000210:Acute-Phase Reaction / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004789:Enzyme Activation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D051379:Mice; D015688:Oncogene Protein pp60(v-src) / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D019947:Receptors, Interleukin-6 / Q000502:physiology; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D012995:Solubility; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000093242:Interleukin-6 Inhibitors
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D015688:Oncogene Protein pp60(v-src); D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D019947:Receptors, Interleukin-6; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D000093242:Interleukin-6 Inhibitors; C108944:SOCS1 protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse