Effect of Oncogenes Upon the Signal Transducer and Activator of Transcription-3 (Stat3) and the Dominant-Negative Isoform Stat3β
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Stat3 is activated by cytokine receptors and non-receptor kinases and plays an etiological role in neoplasia. Stat3 activation entails phosphorylation at the tyrosine 705 residue (Y705), dimerization through a reciprocal SH2 domain-phosphotyrosine interactions, and nuclear translocation. This cascade triggers transcription of genes involved primarily in survival. Our lab recently demonstrated that engagement of cadherins, cell-cell adhesion molecules, triggers a dramatic increase in Stat3 activity, through Rac/Cdc42, IL6 and Jak. Full-length Stat3, termed Stat3α, has an SH2 domain, Y705 residue, and a COOH terminus containing the transcription activation domain (TAD). Stat3β is a naturally-occurring splice variant lacking the TAD. Therefore, Stat3β is defective in transcriptional activation, and competitively inhibits Stat3α signaling. Given the sequence identity around the critical Y705 in Stat3α and Stat3β, we initially set out to examine the phosphorylation pattern of the two isoforms in cells expressing two representative oncogenes, Simian Virus 40 Large Tumor antigen (SVLT) or activated Src (vSrc). My results demonstrate that extensive cell-cell adhesion brought about by cultured cell confluence results in phosphorylation of Stat3α preferentially. On the other hand, SVLT and vSrc expression result in a preferential phosphorylation of Stat3β, although to a much lesser extent by vSrc. The increase in Stat3β phosphorylation by SVLT could be attributed, in part, to an increase in total Stat3β protein levels, brought about through an increase in the levels of the adenine deaminase acting on RNA-1 (ADAR1). In addition, β-pY705-Stat3 turnover is much slower than that of α-pY705- Stat3, leading to accumulation and increased detection. In any event, this increase β-pY705-Stat3 that reduces the activity of Stat3α inhibits transformation by SVLT and triggers apoptosis in transformed cells. Therefore, Stat3β is a naturally occurring variant which is able to curb transformation by oncogenes that require Stat3 function as part of their mechanism of action, a finding which could have important implications in cancer therapy.