Binding and phosphorylation of Par-4 by Akt is essential for cancer cell survival

Anindya Goswami; Ravshan Burikhanov; Aurelie De Thonel; Naoya Fujita; Mamta Goswami; Yanming Zhao; John E. Eriksson; Takashi Tsuruo; Vivek M. Rangnekar

doi:10.1016/j.molcel.2005.08.016

Binding and phosphorylation of Par-4 by Akt is essential for cancer cell survival

Anindya Goswami
, Ravshan Burikhanov
, Aurelie De Thonel
, Naoya Fujita
, Mamta Goswami
, Yanming Zhao
, John E. Eriksson
, Takashi Tsuruo
, Vivek M. Rangnekar

Markey Cancer Center / Cancer Research Priority Initiative

Research output: Contribution to journal › Article › peer-review

135 Scopus citations

Abstract

Activation of the PI3K-Akt pathway by loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, increased growth factor signaling, or oncogene expression renders cancer cells resistant to apoptotic signals and promotes tumor growth. Although Akt acts as a global survival signal, the molecular circuits of this pathway have not been completely established. We report that Akt physically binds to the pro-apoptotic protein Par-4 via the Par-4 leucine zipper domain and phosphorylates Par-4 to inhibit apoptosis. Suppression of Akt activation by the PI3K-inhibitor PTEN or LY294002, Akt expression by RNA-interference, or Akt function by dominant-negative Akt caused apoptosis in cancer cells. Apoptosis induced by inhibiting Akt was blocked by inhibition of Par-4 expression, but not by inhibition of other apoptosis agonists that are Akt substrates, suggesting that inhibition of the PI3K-Akt pathway leads to Par-4-dependent apoptosis. Thus, Par-4 is essential for PTEN-inducible apoptosis, and inactivation of Par-4 by Akt promotes cancer cell survival.

Original language	English
Pages (from-to)	33-44
Number of pages	12
Journal	Molecular Cell
Volume	20
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2005.08.016
State	Published - Oct 7 2005

Bibliographical note

Funding Information:
This study was supported by National Institutes of Health and National Cancer Institute grants CA60872, CA105453, and CA84511 (to V.M.R.). We thank William R. Sellers (Dana-Farber Cancer Institute) for thoughtful suggestions during the preparation of the manuscript.

Funding

This study was supported by National Institutes of Health and National Cancer Institute grants CA60872, CA105453, and CA84511 (to V.M.R.). We thank William R. Sellers (Dana-Farber Cancer Institute) for thoughtful suggestions during the preparation of the manuscript.

Funders	Funder number
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	CA84511, R01CA105453, CA60872
National Childhood Cancer Registry – National Cancer Institute

UN SDGs

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

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2005.08.016

Cite this

@article{a84c08a58e724e8780b89647037dbf39,

title = "Binding and phosphorylation of Par-4 by Akt is essential for cancer cell survival",

abstract = "Activation of the PI3K-Akt pathway by loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, increased growth factor signaling, or oncogene expression renders cancer cells resistant to apoptotic signals and promotes tumor growth. Although Akt acts as a global survival signal, the molecular circuits of this pathway have not been completely established. We report that Akt physically binds to the pro-apoptotic protein Par-4 via the Par-4 leucine zipper domain and phosphorylates Par-4 to inhibit apoptosis. Suppression of Akt activation by the PI3K-inhibitor PTEN or LY294002, Akt expression by RNA-interference, or Akt function by dominant-negative Akt caused apoptosis in cancer cells. Apoptosis induced by inhibiting Akt was blocked by inhibition of Par-4 expression, but not by inhibition of other apoptosis agonists that are Akt substrates, suggesting that inhibition of the PI3K-Akt pathway leads to Par-4-dependent apoptosis. Thus, Par-4 is essential for PTEN-inducible apoptosis, and inactivation of Par-4 by Akt promotes cancer cell survival.",

author = "Anindya Goswami and Ravshan Burikhanov and \{De Thonel\}, Aurelie and Naoya Fujita and Mamta Goswami and Yanming Zhao and Eriksson, \{John E.\} and Takashi Tsuruo and Rangnekar, \{Vivek M.\}",

note = "Funding Information: This study was supported by National Institutes of Health and National Cancer Institute grants CA60872, CA105453, and CA84511 (to V.M.R.). We thank William R. Sellers (Dana-Farber Cancer Institute) for thoughtful suggestions during the preparation of the manuscript. ",

year = "2005",

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doi = "10.1016/j.molcel.2005.08.016",

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AU - Goswami, Anindya

AU - Burikhanov, Ravshan

AU - De Thonel, Aurelie

AU - Fujita, Naoya

AU - Goswami, Mamta

AU - Zhao, Yanming

AU - Eriksson, John E.

AU - Tsuruo, Takashi

AU - Rangnekar, Vivek M.

N1 - Funding Information: This study was supported by National Institutes of Health and National Cancer Institute grants CA60872, CA105453, and CA84511 (to V.M.R.). We thank William R. Sellers (Dana-Farber Cancer Institute) for thoughtful suggestions during the preparation of the manuscript.

PY - 2005/10/7

Y1 - 2005/10/7

N2 - Activation of the PI3K-Akt pathway by loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, increased growth factor signaling, or oncogene expression renders cancer cells resistant to apoptotic signals and promotes tumor growth. Although Akt acts as a global survival signal, the molecular circuits of this pathway have not been completely established. We report that Akt physically binds to the pro-apoptotic protein Par-4 via the Par-4 leucine zipper domain and phosphorylates Par-4 to inhibit apoptosis. Suppression of Akt activation by the PI3K-inhibitor PTEN or LY294002, Akt expression by RNA-interference, or Akt function by dominant-negative Akt caused apoptosis in cancer cells. Apoptosis induced by inhibiting Akt was blocked by inhibition of Par-4 expression, but not by inhibition of other apoptosis agonists that are Akt substrates, suggesting that inhibition of the PI3K-Akt pathway leads to Par-4-dependent apoptosis. Thus, Par-4 is essential for PTEN-inducible apoptosis, and inactivation of Par-4 by Akt promotes cancer cell survival.

AB - Activation of the PI3K-Akt pathway by loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) function, increased growth factor signaling, or oncogene expression renders cancer cells resistant to apoptotic signals and promotes tumor growth. Although Akt acts as a global survival signal, the molecular circuits of this pathway have not been completely established. We report that Akt physically binds to the pro-apoptotic protein Par-4 via the Par-4 leucine zipper domain and phosphorylates Par-4 to inhibit apoptosis. Suppression of Akt activation by the PI3K-inhibitor PTEN or LY294002, Akt expression by RNA-interference, or Akt function by dominant-negative Akt caused apoptosis in cancer cells. Apoptosis induced by inhibiting Akt was blocked by inhibition of Par-4 expression, but not by inhibition of other apoptosis agonists that are Akt substrates, suggesting that inhibition of the PI3K-Akt pathway leads to Par-4-dependent apoptosis. Thus, Par-4 is essential for PTEN-inducible apoptosis, and inactivation of Par-4 by Akt promotes cancer cell survival.

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Binding and phosphorylation of Par-4 by Akt is essential for cancer cell survival

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

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