Tyrosine docking sites of the rat prolactin receptor required for association and activation of stat5.
Prolactin (PRL) interacts with a single chain prolactin-specific receptor of the cytokine receptor superfamily. PRL triggers activation of Jak2 kinase which phosphorylates the PRL receptor itself and the mammary gland factor, Stat5, a member of the family of signal transducers and activators of transcription (Stat). Selection of the particular substrate (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 was abolished in 293 fibroblasts expressing PRL receptor mutants lacking all intracellular tyrosines. We have identified tyrosine phosphorylation sites of the PRL receptor (residues 580, 479, and 473) necessary for maximal Stat5 activation and subsequent Stat5-dependent gene transcription. Moreover, we have shown that none of the tyrosine residues of the PRL receptor are implicated in activation of Jak2. This study demonstrates that only specific tyrosines in the PRL receptor are phosphorylated and are in fact utilized differentially for Stat5-mediated transcriptional signaling.
Pezet
A
A
INSERM U344-Endocrinologie Moléculaire, Faculté de Medecine Necker Enfants Malades, 156 rue de Vaugirard, 75730 Paris Cedex 15, France.
Ferrag
F
F
Kelly
P A
PA
Edery
M
M
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D017930:Genes, Reporter; D019382:Human Growth Hormone / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2; D008894:Milk Proteins; D008961:Models, Structural; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011388:Prolactin / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D011981:Receptors, Prolactin / Q000737:chemistry* / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014443:Tyrosine
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019382:Human Growth Hormone; D019000:Phosphotyrosine; D014443:Tyrosine; D011388:Prolactin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507927:Jak2 protein, rat; D053614:Janus Kinase 2