PMID- 10542266
OWN - NLM
STAT- MEDLINE
DCOM- 19991213
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 45
DP  - 1999 Nov 5
TI  - Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol
      3-Kinase/AKT in breast cancer cells.
PG  - 32274-8
AB  - 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.
FAU - Altiok, S
AU  - Altiok S
AD  - Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard 
      Institutes of Medicine, Boston, Massachusetts 02115, USA.
FAU - Batt, D
AU  - Batt D
FAU - Altiok, N
AU  - Altiok N
FAU - Papautsky, A
AU  - Papautsky A
FAU - Downward, J
AU  - Downward J
FAU - Roberts, T M
AU  - Roberts TM
FAU - Avraham, H
AU  - Avraham H
LA  - eng
GR  - CA76226/CA/NCI NIH HHS/United States
GR  - HL51456/HL/NHLBI NIH HHS/United States
GR  - HL55445/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (BRCA1 Protein)
RN  - 0 (Neuregulin-1)
RN  - 0 (Nuclear Localization Signals)
RN  - 2ZD004190S (Threonine)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
SB  - IM
MH  - BRCA1 Protein/*metabolism
MH  - Breast Neoplasms/*metabolism
MH  - Female
MH  - Humans
MH  - Neuregulin-1/*metabolism
MH  - Nuclear Localization Signals
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
MH  - Threonine/metabolism
MH  - Tumor Cells, Cultured
EDAT- 1999/11/05 00:00
MHDA- 1999/11/05 00:01
CRDT- 1999/11/05 00:00
PHST- 1999/11/05 00:00 [pubmed]
PHST- 1999/11/05 00:01 [medline]
PHST- 1999/11/05 00:00 [entrez]
AID - 10.1074/jbc.274.45.32274 [doi]
AID - S0021-9258(19)51554-X [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Nov 5;274(45):32274-8. doi: 10.1074/jbc.274.45.32274.