DIFFERENTIAL ACTIVATION OF STAT3 AND STAT5 BY DISTINCT REGIONS OF THEGROWTH-HORMONE RECEPTOR

The GH receptor (GHR) is a member of the cytokine receptor superfamily ; its signaling involves the activation of Janus tyrosine kinases (JAK 2) and Stat (signal transducers and activators of transcription) trans cription factors, Using truncated and tyrosine mutants of the receptor , we show that different receptor domains are essential for the activa tion of Stat3 and State. GH-dependent phosphorylation of JAK2, Stat3, and State, as well as transactivation studies with reporter genes cont aining Stat3 and State DNA-binding elements, was performed in cells ex pressing the various GHR mutants. The membrane-proximal region of the receptor necessary for JAK2 activation is sufficient for Stat3 activat ion. In contrast, C-terminal tyrosine residues of GHR are absolutely r equired for State activation. The same residues are also involved in t he regulation of JAK2 dephosphorylation, possibly through the activati on of a phosphatase. Using in vitro experiments with glutathione-S-tra nsferase-fusion proteins, we demonstrate that the SH2 domain of Stat5 binds to the carboxy-terminal tyrosine-phosphorylated residues of GHR. Our results show that a cytokine receptor can mediate differently the activation of distinct Stat proteins that could be involved in cytoki ne-specific effects.