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Related Experiment Videos

Modulation of growth factor receptor function by isoform heterodimerization

W P Chang1, C V Clevenger

  • 1Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, 19104, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 11, 1996
PubMed
Summary

The short prolactin receptor (PRLr-S) isoform acts as a dominant negative, inhibiting signaling and proliferation. Only intermediate prolactin receptor (PRLr-I) homodimers mediate ligand-induced signaling and cellular growth.

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Area of Science:

  • Cell Biology
  • Molecular Endocrinology
  • Signal Transduction

Background:

  • Prolactin receptor (PRLr) signaling is crucial for various cellular functions.
  • Three PRLr isoforms (short, intermediate, long) exist but their heterodimerization effects are unknown.
  • Understanding isoform interactions is key to deciphering PRLr-mediated cellular responses.

Purpose of the Study:

  • To investigate the functional consequences of prolactin receptor (PRLr) isoform heterodimerization.
  • To determine if heterodimeric PRLr complexes can mediate ligand-induced signaling and cellular proliferation.
  • To elucidate the role of specific PRLr isoforms in downstream signaling pathways.

Main Methods:

  • Constructed chimeric receptors using GM-CSF receptor (GM-CSFr) extracellular domains and rat PRLr intracellular domains (PRLr-I, PRLr-S).

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  • Utilized Ba/F3 cell line for stable transfection and expression analysis via Northern blot and immunoprecipitation.
  • Assessed receptor binding using flow cytometry with phycoerythrin-conjugated GM-CSF and measured proliferation via [3H]thymidine incorporation.

    • Main Results:

    • Chimeric receptors expressing GM-CSFr/PRLr-I homodimers showed significant proliferation and Jak2/Fyn kinase activation upon GM-CSF stimulation.
    • Transfectants with GM-CSFr/PRLr-S homodimers or GM-CSFr/PRLr-S+1 heterodimers did not proliferate or activate kinases.
    • PRLr-S isoform demonstrated dominant negative effects, inhibiting signaling and proliferation mediated by the receptor complex.

    Conclusions:

    • The intermediate prolactin receptor (PRLr-I) isoform is essential for Jak2 and Fyn activation and subsequent proliferation.
    • The short prolactin receptor (PRLr-S) isoform acts as a dominant negative regulator, suppressing PRLr signaling.
    • Specific structural motifs in the PRLr-I carboxy terminus are required for kinase activation, and these are absent in PRLr-S.