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SRC family kinases accelerate prolactin receptor internalization, modulating trafficking and signaling in breast

Timothy M Piazza1, Juu-Chin Lu, Kristopher C Carver

  • 1Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin 53706, USA.

Molecular Endocrinology (Baltimore, Md.)
|December 6, 2008
PubMed

Insights

Prolactin (PRL) down-regulates its long receptor (lPRLR) in breast cancer cells via src family kinases (SFKs) and dynamin-2-mediated endocytosis, selectively impacting ERK1/2 and Akt signaling.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Endocrinology

Background:

  • Prolactin (PRL) plays a role in human breast cancer, but its regulation of its own receptor (PRLR) is poorly understood.
  • Ligand-initiated endocytosis is crucial for receptor regulation and signaling, potentially contributing to oncogenesis.
  • Exogenous PRL accelerates long PRL receptor (lPRLR) degradation, but the underlying signals and downstream pathways in breast cancer cells remain unclear.

Purpose of the Study:

  • To elucidate the signaling pathways and mechanisms by which prolactin (PRL) induces the internalization and down-regulation of its long receptor (lPRLR) in breast cancer cells.
  • To investigate the role of src family kinases (SFKs) and endocytosis in PRL-induced lPRLR regulation and downstream signaling.

Main Methods:

  • Utilized MCF-7 breast cancer cells.
  • Investigated the effect of src family kinases (SFKs) and Janus kinase 2 inhibition on PRL-induced lPRLR down-regulation.
  • Examined the association of lPRLR with SFKs in lipid rafts.
  • Assessed the role of dynamin-2 and endocytosis in lPRLR internalization and signaling.
  • Analyzed the phosphorylation of downstream signaling molecules like ERK1/2, Akt, Janus kinase 2, and signal transducer and activator of transcription 5.

Main Results:

  • PRL-induced lPRLR down-regulation was significantly reduced by SFK inhibition, but not by Janus kinase 2 inhibition.
  • SFK inhibition led to the accumulation of a PRLR extracellular domain fragment, suggesting involvement in newly synthesized receptor processing.
  • lPRLR constitutively associated with SFKs within lipid rafts.
  • PRL-induced SFK activation promoted dynamin-2 recruitment, leading to lPRLR endocytosis, which was essential for its down-regulation.
  • Endocytosis was required for optimal phosphorylation of ERK1/2 and Akt, but not for Janus kinase 2 or signal transducer and activator of transcription 5.

Conclusions:

  • Src family kinases (SFKs) are critical mediators of prolactin (PRL)-initiated lPRLR internalization and down-regulation in breast cancer cells.
  • Ligand-induced endocytosis of lPRLR is essential for modulating specific downstream signaling pathways, including ERK1/2 and Akt.
  • These findings highlight the importance of SFKs and receptor trafficking in PRL signaling within the context of breast cancer.

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