Regulation of STAT3 by direct binding to the Rac1 GTPase

The signal transducers and activators of transcription (STAT) transcription factors become phosphorylated on tyrosine and translocate to the nucleus a fter stimulation of cells with growth factors or cytokines. We show that th e Rad guanosine triphosphatase can bind to and regulate STAT3 activity. Dom inant negative Rad inhibited STAT3 activation by growth factors, whereas ac tivated Rad stimulated STAT3 phosphorylation on both tyrosine and serine re sidues. Moreover, activated Rad formed a complex with STAT3 in mammalian ce lls, Yeast two-hybrid analysis indicated that STAT3 binds directly to activ e but not inactive Rad and that the interaction occurs via the effector dom ain. Rad may serve as an alternate mechanism for targeting STAT3 to tyrosin e kinase signaling complexes.