JAK2 AND STAT5, BUT NOT JAK1 AND STAT1, ARE REQUIRED FOR PROLACTIN-INDUCED BETA-LACTOGLOBULIN TRANSCRIPTION

Several different Janus kinases (JAKs) and signal transducers and acti vation of transcription (STATs) have been implicated in mediating the biological responses induced by PRL, based on their ligand-dependent t yrosine phosphorylation and activation. However, these criteria alone do not prove that a particular JAK or STAT is essential for signal tra nsduction. We have used mutant cell lines defective in JAK1, JAK2, or STAT1 to examine their roles in PRL-dependent signaling. JAK2 is absol utely required for PRL-dependent phosphorylation of the receptor, acti vation of STATs, and induction of beta-lactoglobulin. Wild type, but n ot kinase-negative JAK2, restores all responses to PRL in JAK2-defecti ve cells, suggesting that JAK2 function, not merely the protein, is re quired. In contrast, JAK1, which is phosphorylated in response to PRL, is not required for any of these functions. Although STAT1 homodimers do form in response to PRL, no defect in PRL-dependent signaling is a pparent when STAT1 is missing, suggesting that STAT5, which is strongl y activated in response to PRL, is primarily responsible for driving t he expression of PRL-responsive genes.