Oncogene-mediated inhibition of glycogen synthase kinase 3 beta impairs degradation of prolactin receptor.

Prolactin receptors (PRLr) expressed in a majority of breast cancer are activated by prolactin and growth hormone. The PRLr is commonly stabilized in human breast cancer due to decreased phosphorylation of residue Ser(349), which, when phosphorylated, recruits the beta Trcp E3 ubiquitin ligase and facilitates PRLr degradation. Here, we show that constitutive oncogenic signaling downstream of ErbB2 and Ras stabilizes PRLr via inhibitory phosphorylation of glycogen synthase kinase-3beta (GSK3 beta) on Ser(9). Importantly, inactivation of GSK3 beta correlates with elevated levels of PRLr protein in clinical human breast cancer specimens. Additional studies using pharmacologic, biochemical, and genetic approaches reveal that GSK3 beta is a bona fide PRLr kinase that phosphorylates PRLr on Ser(349) and is required for the recognition of PRLr by beta Trcp, as well as for PRLr ubiquitination and degradation.