A25
Stat3 is activated upon amplification of fibroblast growth factor receptors
Anna Dudka, Steve Sweet, John Heath
University of Birmingham, UK
Fibroblast growth factor receptors (FGFRs) play key roles in development, cell proliferation and differentiation. They possess intrinsic tyrosine kinase activity which enables activation of other signaling proteins, formation of multiprotein signaling complexes and activation of downstream cascades including the Ras/MAPK pathway. Here we identify signal transducer and activator of transcription 3 (STAT3) as a novel partner for FGFR1, using a proteomic approach. STAT3 binds FGFR1 in a phospho-dependent manner. Phosphorylated Tyr677, within the intracellular domain of FGFR1, is proved to be critical for this association. Furthermore, we show that STAT3 tyrosine phosphorylation requires over-expression of FGFRs, as shown in the breast cancer cell line, SUM52-PE. STAT3 activation leads to nuclear accumulation of STAT3 and expression of early response transcription factors, JunB and c-myc. This activity is significantly decreased upon experimental over-expression of the site-specific tyrosine mutant Y677F FGFR1 in HEK293T and HeLa cell lines. The inhibition of Src kinase decreases FGF1-induced STAT3 activation via tyrosine phosphorylation. However, the involvement of JAKs in FGFRs-mediated TyrSTAT3 activation is cell type-dependent. Finally, STAT3 is additionally activated through serine phosphorylation by JNK and ERK kinases, which are induced by FGF1 stimulation. Since over-expression of FGFRs is common in several tumours and STAT3 is a well known oncogene, it is possible that the FGFR-STAT3 signaling pathway is up-regulated in cancer cells and therefore merits consideration as a therapeutic target.
