PROLINE-RICH SEQUENCE-MEDIATED JAK2 ASSOCIATION TO THE PROLACTIN RECEPTOR IS REQUIRED BUT NOT SUFFICIENT FOR SIGNAL-TRANSDUCTION

The prolactin receptor (PRLR) belongs to the superfamily of cytokine/g rowth hormone/prolactin receptors. Members of this family do not conta in a tyrosine kinase domain but are associated with cytoplasmic kinase s of the Jak family. Here, we examine different mutants of the PRLR wi th respect to their ability to associate and activate the kinase Jak2 and the transcription factor Stat1. Moreover, using a biological assay system we are able to correlate these activities with activation of p rolactin-responsive gene transcription. Our results indicate that inte raction between Jak2 and PRLR requires a proline-rich sequence in the membrane proximal region of the receptor, which is conserved among the different members of the cytokine receptor superfamily. We also show that association of Jak2 with the receptor is sufficient for activatio n of the kinase as well as the transcription factor Stat1. Moreover, o ur findings indicate that association of PRLR with Jak2 is necessary b ut not sufficient for the transmission of a lactogenic signal. We have identified two other cytoplasmic regions of the PRLR that are require d for activation of transcription. These two regions are located betwe en boxes 1 and 2 and are in the carboxyl-terminal tail of the receptor . These sites probably involve specific interactions with other effect or molecules.