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Molecular and Cellular Biology, May 2004, p. 4038-4048, Vol. 24, No. 9
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.9.4038-4048.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Ying Li,1 K. G. Suresh Kumar,1 Weigang Tang,1 Vladimir S. Spiegelman,2 and Serge Y. Fuchs1*

Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1 AMC Cancer Center, Lakewood, Colorado 802142

Received 24 November 2003/ Returned for modification 22 December 2003/ Accepted 10 February 2004

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 ß-TrCP2, which functions as a substrate recognition subunit of the SCFß-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 SCFß-TrCP. The PRLRS349A mutant is resistant to ubiquitination and is more stable than its wild-type counterpart. Phosphorylated PRLR undergoes ubiquitination by SCFß-TrCP in vitro. Knockdown of ß-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 SCFß-TrCP substrate and implicate ß-TrCP as an important negative regulator of PRL signaling and cellular responses to this hormone.

* Corresponding author. Mailing address: Department of Animal Biology, University of Pennsylvania, 3800 Spruce St., Room 161E, Philadelphia, PA 19104-6046. Phone: (215) 573-6949. Fax: (215) 573-5188. E-mail: syfuchs{at}vet.upenn.edu.

Molecular and Cellular Biology, May 2004, p. 4038-4048, Vol. 24, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.9.4038-4048.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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