TYROSINE DOCKING SITES OF THE RAT PROLACTIN RECEPTOR REQUIRED FOR ASSOCIATION AND ACTIVATION OF STAT5

Prolactin (PRL) interacts with a single chain prolactin-specific recep tor of the cytokine receptor superfamily. PRL triggers activation of J ak2 kinase which phosphorylates the PRL receptor itself and the mammar y gland factor, Stat5, a member of the family of signal transducers an d activators of transcription (Stat). Selection of the particular subs trate (Stat 5), that is characterized by transcriptional responses to PRL, has been shown to be determined by specific tyrosine-based motifs common to many cytokine receptors. PRL-induced activation of Stat5 wa s abolished in 293 fibroblasts expressing PRL receptor mutants lacking all intracellular tyrosines. We have identified tyrosine phosphorylat ion sites of the PRL receptor (residues 580, 479, and 473) necessary f or maximal Stat5 activation and subsequent Stat5-dependent gene transc ription. Moreover, we have shown that none of the tyrosine residues of the PRL receptor are implicated in activation of Jak2. This study dem onstrates that only specific tyrosines in the PRL receptor are phospho rylated and are in fact utilized differentially for Stat5-mediated tra nscriptional signaling.