ACTIVATION OF STAT3 BY THE C-FES PROTEIN-TYROSINE KINASE

STATs (signal transducers and activators of transcription) are transcr iption factors that contain SH2 domains and are activated by tyrosine phosphorylation, often in response to cytokine stimulation. Recent evi dence indicates that the transforming tyrosine kinases encoded by the v-Src, v-Abl, and v-Fps oncogenes can induce STAT activation, suggesti ng that their normal cellular homologs may contribute to STAT activati on under physiological conditions, In this report, we provide direct e vidence that c-Fes, the normal human homolog of v-Fps, potently activa tes STAT3, Transient transfection of human 293T cells with STAT3 and F es resulted in strong stimulation of STAT3 DNA binding activity. In co ntrast, only modest activation of STATE by Fes was observed in this sy stem, indicative of possible selectivity, To determine whether Fes ind uced STAT3 activation is dependent upon endogenous mammalian kinases, co-expression studies were also performed in Sf-9 insect cells, Fes al so induced a dramatic increase in STAT3 DNA binding activity in this s ystem, whereas no activation of STAT5 was observed. As a positive cont rol, both STAT3 and STATE were shown to be activated by the Bcr-Abl ty rosine kinase in Sf-9 cells, Fes induced strong tyrosine phosphorylati on of STETS in both expression systems, consistent with the gel-shift results, Fes and STAT3 have been independently linked to myeloid diffe rentiation. Results presented here suggest that these proteins may coo perate to promote differentiation signaling in response to hematopoiet ic cytokines.