The Journal of biological chemistry
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The SH2 domain containing signal transducers and activators of transcription (Stat proteins) are effector molecules downstream of cytokine receptors. Ligand/receptor engagement triggers Stat proteins tyrosine phosphorylation, dimerization, and translocation to the nucleus where they regulate gene transcription. Stat5, originally identified as a mammary gland growth factor, is an essential mediator of prolactin (PRL)-induced milk protein gene activation. ⋯ Furthermore, using different forms natural forms of the PRLR as well as receptor tyrosine to phenylalanine mutant forms, we determined that tyrosine phosphorylation of Stat5 is independent of PRLR phosphotyrosines. We established, however, that the C-terminal tyrosine of the PRLR Nb2 form, Tyr382, plays an essential positive role in PRLR-dependent Stat5 nuclear translocation and subsequently DNA binding. All together, our data propose a new model for activation of Stat5 through the PRLR, suggesting that Stat5 tyrosine phosphorylation and nuclear translocation are two separately regulated events.