A Critical Role for Lysine 685 in Gene Expression Mediated by Unphosphorylated STAT3 [Signal Transduction]

September 12th, 2014 by Dasgupta, M., Unal, H., Willard, B., Yang, J., Karnik, S. S., Stark, G. R.

STAT3 is a pleiotropic transcription factor that is activated by the phosphorylation of tyrosine 705 in response to many cytokines and growth factors. STAT3 without Y705 phosphorylation (U-STAT3) is also a potent transcription factor, and its concentration in cells increases greatly in response to STAT3 activation, since the STAT3 gene can be driven by phosphorylated STAT3 dimers. We have now searched for post-translational modifications of U-STAT3 that might have a critical role in its function. An analysis by mass spectroscopy indicated that U-STAT3 is acetylated on K685, and the integrity of K685 is required for the expression of most U-STAT3-dependent genes. In contrast, we found only a very minor role for K685 in gene expression induced in response to tyrosine-phosphorylated STAT3. U-STAT3 plays an important role in angiotensin II-induced gene expression and in the consequent development of cardiac hypertrophy and dysfunction. Mutation of K685 inhibits this function of STAT3, providing new information on the role of U-STAT3 in augmenting the development of heart failure.