Abstract
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.
Highlights
TRK oncogenes, isolated from papillary thyroid tumors [1], represent rearranged versions of the NTRK1 gene, coding for Nerve Growth Factor (NGF) receptor, named TRKA
We have previously shown that TRK oncogenes, chimeric versions of the TRKA receptor containing its tyrosine kinase domain [30], induce neuronal like differentiation of PC12 cells mimicking the effect of NGF treatment [3]
To investigate whether STAT3 is involved in signalling of TRK oncogenes, we analyzed Stat3 phosphorylation status by Western blot analysis with anti-phosphoSTAT3 serine 727 (S727) and Y705 antibodies in PC12 cells transiently transfected with TRK oncogenes (Figure 1A)
Summary
TRK oncogenes, isolated from papillary thyroid tumors [1], represent rearranged versions of the NTRK1 gene, coding for Nerve Growth Factor (NGF) receptor, named TRKA. TRK oncoproteins display constitutive tyrosine kinase activity, promoted by coiled-coil domains provided by the activating genes [2], mimicking the biochemical and biological effects of NTRK1 receptor activated by NGF [3,4]. The mechanism of action of TRK oncoproteins and their intracellular signal transduction has been in part elucidated. This has been performed by expressing the TRK oncogenes in different mammalian cell systems; among these, NIH3T3 and PC12 cell lines, which represent a useful model for studying in vitro oncogenetriggered transformation and neuronal-like differentiation, respectively [3,4]. More studies are required in order to fully dissect the mechanism of action of TRK oncogenes
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