title: Constitutive activation of Jak-2 and Tyk-2 in a v-Src-transformed human gallbladder adenocarcinoma cell line.
abstract: It is well known that v-Src phosphorylates various substrates on tyrosine residue and associates with tyrosine-phosphorylated proteins as well as proline-rich ligands through its SH2 and SH3 domains, respectively, thereby inducing oncogenic transformation. A signal pathway from the cell surface to genes in the nucleus, the Jak/STAT (signal transducers and activators of transcription) pathway, has been shown to be involved in the signal transduction mechanism mediated by many cytokines and growth factors. Although a member of the STAT family, STAT3 has been reported to be constitutively activated in several v-Src-transformed cells, and it still remains unknown whether Jak molecules, which act upstream of STATs, are involved in the v-Src-induced activation mechanism of STAT3. In this study, we analyzed activations of both Jak and STAT molecules using v-Src-transformed HAG-1 cells derived from a human gallbladder adenocarcinoma. STAT3 was found to be constitutively activated in v-Src-transformed HAG-1 cells, but not in either non-transformed mock-transfected or activated c-H-ras-transfected HAG-1 cells, even though the other known STAT molecules are expressed. Furthermore, both Jak-2 and Tyk-2 were constitutively activated only in v-Src-transformed HAG-1 cells. Association of v-Src with either STAT3 or the Jak molecules was not observed. No change of this activation was detected by either interferon (IFN)-alpha2a or IFN-gamma, which had shown inhibitory effects on the growth of v-Src-transformed HAG-1 cells. These results raise the possibility that Jak-2 and Tyk-2 are both activated by v-Src, thereby contributing to the constitutive activation of STAT3 in the v-Src-transformed cells.
authors.affiliation: Department of Human Genetics, National Institute of Genetics, Shizuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Murakami
authors.forename: S
authors.initials: S
authors.lastname: Nakano
authors.forename: Y
authors.initials: Y
authors.lastname: Niho
authors.forename: N
authors.initials: N
authors.lastname: Hamasaki
authors.forename: K
authors.initials: K
authors.lastname: Izuhara
mesh_terms: D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005706:Gallbladder Neoplasms / Q000378:metabolism*; D016391:Genes, src / Q000235:genetics*; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D053616:Janus Kinase 3; D009687:Nuclear Proteins / Q000032:analysis; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011506:Proteins / Q000502:physiology*; D050796:STAT3 Transcription Factor; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000502:physiology; D014170:Transformation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011506:Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D019000:Phosphotyrosine; D007372:Interferons; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D053634:TYK2 Kinase; C070139:TYK2 protein, human