Role of STAT3 in in vitro transformation triggered by TRK oncogenes

• Published in: PloS one Vol. 5; no. 3; p. e9446
• Main Authors: Miranda, Claudia, Fumagalli, Tiziana, Anania, Maria Chiara, Vizioli, Maria Grazia, Pagliardini, Sonia, Pierotti, Marco A, Greco, Angela
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03-03-2010; Public Library of Science (PLoS)
• Subjects: Animals; Breast cancer; Cancer therapies; Cell adhesion & migration; Cell Biology/Cell Signaling; Cell growth; Cell Survival; Cell Transformation, Neoplastic; Cytokines; Gene Expression Regulation, Neoplastic; Genes; Genetic aspects; Genetic transformation; Growth factors; HeLa Cells; Humans; Kinases; MAP kinase; MAP Kinase Signaling System; Medicine; Mice; Molecular Biology; Nerve growth factor; Nervous system; NIH 3T3 Cells; Oncogene Proteins - metabolism; Oncogenes; Oncology; PC12 Cells; Pheochromocytoma cells; Phosphorylation; Protein-tyrosine kinase; Proteins; Rats; Rodents; Signal transduction; Signaling; Stat3 protein; STAT3 Transcription Factor - metabolism; Studies; Thyroid cancer; Transcription; Transformation; TrkA protein; TrkA receptors; Tumors; Tyrosine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0009446

TRK oncoproteins are chimeric versions of the NTRK1/NGF receptor and display constitutive tyrosine kinase activity leading to transformation of NIH3T3 cells and neuronal differentiation of PC12 cells. Signal Transducer and Activator of Transcription (STAT) 3 is activated in response to cytokines and growth factors and it has been recently identified as a novel signal transducer for TrkA, mediating the functions of NGF in nervous system. In this paper we have investigated STAT3 involvement in signalling induced by TRK oncogenes. We showed that TRK oncogenes trigger STAT3 phosphorylation both on Y705 and S727 residues and STAT3 transcriptional activity. MAPK pathway was involved in the induction of STAT3 phosphorylation. Interestingly, we have shown reduced STAT3 protein level in NIH3T3 transformed foci expressing TRK oncogenes. Overall, we have unveiled a dual role for STAT3 in TRK oncogenes-induced NIH3T3 transformation: i) decreased STAT3 protein levels, driven by TRK oncoproteins activity, are associated to morphological transformation; ii) residual STAT3 transcriptional activity is required for cell growth.