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Acetylation modulates prolactin receptor dimerization.

Cytokine-activated receptors undergo extracellular domain dimerization, which is necessary to activate intracellular signaling pathways. Here, we report that in prolactin (PRL)-treated cells, PRL receptor (PRLR) undergoes cytoplasmic loop dimerization that is acetylation-dependent. PRLR-recruited CREB-binding protein (CBP) acetylates multiple lysine sites randomly distributed along the cytoplasmic loop of PRLR. Two PRLR monomers appear to interact with each other at multiple parts from the membrane-proximal region to the membrane-distal region, relying on the coordination among multiple lysine sites neutralized via acetylation. Cytoplasmic loop-dimerized PRLR activates STAT5, which is also acetylated by CBP and undergoes acetylation-dependent dimerization. PRLR dimerization and subsequent signaling are enhanced by treating the cells with deacetylase sirtuin (SIRT) inhibitor nicotinamide or histone deacetylase (HDAC) inhibitor trichostatin A but inhibited by expressing exogenous deacetylase SIRT2 or HDAC6. Our results suggest that acetylation and deacetylation provide the rheostat-like regulation for the cytokine receptor PRLR in its cytoplasmic loop dimerization and subsequent STAT5 activation.

Pubmed ID: 20962278


  • Ma L
  • Gao JS
  • Guan Y
  • Shi X
  • Zhang H
  • Ayrapetov MK
  • Zhang Z
  • Xu L
  • Hyun YM
  • Kim M
  • Zhuang S
  • Chin YE


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

November 9, 2010

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01 DK085065
  • Agency: NHLBI NIH HHS, Id: R01 HL087088

Mesh Terms

  • Acetylation
  • Binding Sites
  • CREB-Binding Protein
  • Cell Line
  • Humans
  • Lysine
  • Protein Multimerization
  • Receptors, Prolactin
  • STAT5 Transcription Factor