Oncogene-mediated inhibition of glycogen synthase kinase 3β 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 βTrcp 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-3β (GSK3β) on Ser ⁹. Importantly, inactivation of GSK3β correlates with elevated levels of PRLr protein in clinical human breast cancer specimens. Additional studies using pharmacologic, biochemical, and genetic approaches reveal that GSK3β is a bona fide PRLr kinase that phosphorylates PRLr on Ser ³⁴⁹ and is required for the recognition of PRLr by βTrcp, as well as for PRLr ubiquitination and degradation.