The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells

Qing Bai She, David B. Solit, Qing Ye, Kathryn E. O'Reilly, Jose Lobo, Neal Rosen

Research output: Contribution to journalArticlepeer-review

367 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)287-297
Number of pages11
JournalCancer Cell
Volume8
Issue number4
DOIs
StatePublished - Oct 2005

Bibliographical note

Funding Information:
We wish to thank Mark Moasser for helping establish the MDA-468TR-PTEN cells; Michael Greenberg for the wild-type BAD and its mutants, BADS112A, BADS136A, and BADS112A/S136A; and Christopher Thomas for SKMG-3 cell line. This work was supported by NIH grant PO1-CA94060, the Taub Foundation, the William H. Goodwin and Alice Goodwin Foundation for Cancer Research, and the MSKCC Experimental Therapeutics Program.

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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