Regulation of the STAT3 transcription factor

The family of transcription factors Signal Transducers and Activators of Transcription (STATs) are key mediators of cytokine signaling. Upon cytokine stimulation, STATs are tyrosine phosphorylated by receptor-associated Janus kinases (JAKs) in the cytoplasm, and subsequently translocate into the nucleus where they bind to target DNA element and induce gene expression. Therefore proper response to cytokine relies on the ability of the STATs to enter or exit the nucleus.; STAT3 is a member of this family that can be activated by a large number of cytokines. In recently years activated STAT3 has also been implicated as an oncoprotein. The dynamic nucleocytoplasmic movement of STAT3 and the molecular mechanism for its nuclear import has been investigated in this study. It is demonstrated that unphosphorylated STAT3 constitutively shuttles into and out of the nucleus. The nuclear import of STAT3 is mediated by a specific soluble import carrier importin-alpha3. A defined sequence in the coiled-coil domain of STAT3 is indispensable for its interaction with importin-alpha proteins and the consequent nuclear translocation. These findings define a distinct mechanism of STAT3 nuclear import in the STAT family that may be targeted for therapeutics.; The constitutive nuclear presence of STAT3 raised the question whether it could be a substrate for nuclear tyrosine kinases. The Breast Tumor Kinase (Brk) is a nuclear tyrosine kinase that is over-expressed in more than 60% of breast carcinoma. The data presented in this dissertation indicate expression of Brk induces activation of STAT3, but not any other members of the STAT family. It is further demonstrated that STAT3 is a direct substrate for Brk. STAT3 activation correlates with Brk expression in breast carcinoma cells. It remains largely unknown how Brk contributes to the development of breast cancer. The identification of STAT3 as a downstream effector should open a new avenue to study Brk-mediated malignant transformation.