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

doi:10.1016/j.ccr.2005.09.006

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 journal › Article › peer-review

369 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 language	English
Pages (from-to)	287-297
Number of pages	11
Journal	Cancer Cell
Volume	8
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2005.09.006
State	Published - 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
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2005.09.006

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

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.",

author = "She, {Qing Bai} and Solit, {David B.} and Qing Ye and O'Reilly, {Kathryn E.} and Jose Lobo and Neal Rosen",

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. ",

year = "2005",

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doi = "10.1016/j.ccr.2005.09.006",

language = "English",

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AU - She, Qing Bai

AU - Solit, David B.

AU - Ye, Qing

AU - O'Reilly, Kathryn E.

AU - Lobo, Jose

AU - Rosen, Neal

N1 - 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.

PY - 2005/10

Y1 - 2005/10

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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