The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells.
Tumor cells with mutated PTEN proliferate in an EGFR-independent manner. Induction of PTEN sensitizes cells to EGFR inhibition, and the combination causes synergistic apoptosis. Synergy is due to inhibition of two parallel pathways that phosphorylate the proapoptotic protein BAD at distinct sites. Serine 112 phosphorylation is EGFR/MEK/MAPK dependent, whereas serine 136 phosphorylation is PI3K/Akt dependent. Either phosphorylation is sufficient to sequester BAD to 14-3-3. BAD is released and apoptosis is induced only if both serines are dephosphorylated in response to inhibition of both pathways. Reduction of BAD expression by RNA interference prevents apoptosis in response to pathway inhibition. Thus, BAD integrates the antiapoptotic effects of both pathways. Combined inhibition of EGFR and PI3K signaling may be a useful therapeutic strategy.
She
Qing-Bai
QB
Program in Molecular Pharmacology and Chemistry, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Solit
David B
DB
Ye
Qing
Q
O'Reilly
Kathryn E
KE
Lobo
Jose
J
Rosen
Neal
N
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D051025:bcl-Associated Death Protein
D002352:Carrier Proteins; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D025521:Tumor Suppressor Proteins; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C494820:Bad protein, mouse; C494918:AKT1 protein, human; C494929:PTEN protein, human