Negative Regulation of Prolactin Receptor Stability and Signaling Mediated by SCFβ-TrCP E3 Ubiquitin Ligase

Ying Li, K. G.Suresh Kumar, Weigang Tang, Vladimir S. Spiegelman, Serge Y. Fuchs

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Ubiquitin-dependent degradation of hormone receptors is emerging as a key mechanism that regulates the magnitude and duration of hormonal effects on cells and tissues. The pituitary hormone prolactin (PRL) is involved in regulating cell differentiation, proliferation, and survival. PRL engages its receptor (PRLR) to initiate various signaling cascades, including the phosphorylation and activation of Stat5. We found that PRL promotes interaction between PRLR and the F-box protein β-TrCP2, which functions as a substrate recognition subunit of the SCFβ-TrCP E3 ubiquitin ligase. This interaction requires PRLR phosphorylation and the integrity of serine 349 within a conserved motif, which is similar to conserved motifs present in other substrates of SCFβ-TrCP. The PRLRS349A mutant is resistant to ubiquitination and is more stable than its wild-type counterpart. Phosphorylated PRLR undergoes ubiquitination by SCFβ-TrCP in vitro. Knockdown of β-TrCP expression inhibits the ubiquitination and degradation of PRLR and promotes PRL-dependent phosphorylation of Stat5 as well as Stat5-dependent transcription in cells. Furthermore, the activation of Stat5 and the stimulation of cell growth by PRL are augmented in cells expressing the PRLRS349A mutant. These data indicate that PRLR is a novel SCF β-TrCP substrate and implicate β-TrCP as an important negative regulator of PRL signaling and cellular responses to this hormone.

Original languageEnglish (US)
Pages (from-to)4038-4048
Number of pages11
JournalMolecular and cellular biology
Issue number9
StatePublished - May 2004

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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