Format

Send to

Choose Destination
See comment in PubMed Commons below
Mol Cell Biol. 2004 May;24(9):4038-48.

Negative regulation of prolactin receptor stability and signaling mediated by SCF(beta-TrCP) E3 ubiquitin ligase.

Author information

1
Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Abstract

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 beta-TrCP2, which functions as a substrate recognition subunit of the SCF(beta-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 SCF(beta-TrCP). The PRLR(S349A) mutant is resistant to ubiquitination and is more stable than its wild-type counterpart. Phosphorylated PRLR undergoes ubiquitination by SCF(beta-TrCP) in vitro. Knockdown of beta-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 PRLR(S349A) mutant. These data indicate that PRLR is a novel SCF(beta-TrCP) substrate and implicate beta-TrCP as an important negative regulator of PRL signaling and cellular responses to this hormone.

PMID:
15082796
PMCID:
PMC387770
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center