Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells

J Biol Chem. 1999 Nov 5;274(45):32274-8. doi: 10.1074/jbc.274.45.32274.


The breast cancer susceptibility gene BRCA1 encodes a nuclear phosphoprotein that acts as a tumor suppressor. Phosphorylation of BRCA1 has been implicated in altering its function, however, the pathway(s) that leads to the phosphorylation of BRCA1 has not been described. Here, a signaling pathway by which heregulin induces cell cycle-independent phosphorylation of BRCA1 was delineated. We showed that heregulin stimulation induced the phosphorylation of BRCA1 and concomitant activation of the serine/threonine kinase AKT in T47D human breast cancer cells. Heregulin-induced phosphorylation of BRCA1 was abrogated by phosphatidylinositol 3-kinase (PI3K) inhibitors and by a dominant-negative AKT. In the absence of heregulin, the ectopic expression of the constitutively active p110 subunit of PI3K was sufficient to induce BRCA1 phosphorylation. Furthermore, the purified glutathione S-transferase/AKT kinase phosphorylated BRCA1 in vitro. We have also shown that the phosphorylation of BRCA1 by AKT occurs on the residue Thr-509, which is located in the nuclear localization signal. These results reveal a novel signaling pathway that links extracellular signals to the phosphorylation of BRCA1 in breast cancer cells.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • BRCA1 Protein / metabolism*
  • Breast Neoplasms / metabolism*
  • Female
  • Humans
  • Neuregulin-1 / metabolism*
  • Nuclear Localization Signals
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Threonine / metabolism
  • Tumor Cells, Cultured


  • BRCA1 Protein
  • Neuregulin-1
  • Nuclear Localization Signals
  • Threonine
  • Phosphatidylinositol 3-Kinases