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

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.

Pubmed ID: 10542266


  • Altiok S
  • Batt D
  • Altiok N
  • Papautsky A
  • Downward J
  • Roberts TM
  • Avraham H


The Journal of biological chemistry

Publication Data

November 5, 1999

Associated Grants

  • Agency: NCI NIH HHS, Id: CA76226
  • Agency: NHLBI NIH HHS, Id: HL51456
  • Agency: NHLBI NIH HHS, Id: HL55445

Mesh Terms

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