Grb2 downregulation leads to Akt inactivation in heregulin-stimulated and ErbB2-overexpressing breast cancer cells.
ErbB2 can be activated by its own overexpression or be transactivated by the heregulin polypeptide growth factor. Activation of ErbB2 leads to breast cancer cell proliferation, presumably by inducing the activation of extracellular signal-regulated kinases 1,2 (Erk1,2) and Akt. We have previously reported that the growth factor receptor bound protein-2 (Grb2) is required for the proliferation of ErbB2-overexpressing breast cancer cells. We investigated here whether Grb2 protein plays a role in heregulin-stimulated proliferation. Grb2 protein inhibition led to growth inhibition of heregulin-stimulated breast cancer cells, but not Erk1,2 inactivation. These findings are similar to our earlier observations in ErbB2-overexpressing cells. Since Akt can also be activated by heregulin, the effects of Grb2 inhibition on Akt were examined. Akt was inactivated following Grb2 downregulation in heregulin-stimulated breast cancer cells. We then examined the effects of Grb2 downregulation on Akt in ErbB2-overexpressing cells in the absence of heregulin. Similar to heregulin-stimulated cells, Grb2 inhibition also led to Akt inactivation in ErbB2-overexpressing breast cancer cells. Our results indicate that the activation of ErbB2 by heregulin or by its overexpression requires Grb2 to stimulate the Akt pathway to propagate mitogenic signals.
Lim
S J
SJ
Department of Bioimmunotherapy, Section of Immunobiology and Drug Carriers, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Lopez-Berestein
G
G
Hung
M C
MC
Lupu
R
R
Tari
A M
AM
D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation; D005260:Female; D051380:GRB2 Adaptor Protein; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D020890:Neuregulin-1 / Q000235:genetics / Q000494:pharmacology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D008081:Liposomes; D020890:Neuregulin-1; D020319:Oligodeoxyribonucleotides, Antisense; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C495948:GRB2 protein, human; C494918:AKT1 protein, human