FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt

Huadong Pei; Liang Li; Brooke L. Fridley; Gregory D. Jenkins; Krishna R. Kalari; Wilma Lingle; Gloria Petersen; Zhenkun Lou; Liewei Wang

doi:10.1016/j.ccr.2009.07.016

FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt

Huadong Pei, Liang Li, Brooke L. Fridley, Gregory D. Jenkins, Krishna R. Kalari, Wilma Lingle, Gloria Petersen, Zhenkun Lou, Liewei Wang

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

433 Scopus citations

Abstract

Akt is a central regulator of cell growth. Its activity can be negatively regulated by the phosphatase PHLPP that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1). However, how PHLPP is targeted to Akt is not clear. Here we show that FKBP51 (FK506-binding protein 51) acts as a scaffolding protein for Akt and PHLPP and promotes dephosphorylation of Akt. Furthermore, FKBP51 is downregulated in pancreatic cancer tissue samples and several cancer cell lines. Decreased FKBP51 expression in cancer cells results in hyperphosphorylation of Akt and decreased cell death following genotoxic stress. Overall, our findings identify FKBP51 as a negative regulator of the Akt pathway, with potentially important implications for cancer etiology and response to chemotherapy.

Original language	English (US)
Pages (from-to)	259-266
Number of pages	8
Journal	Cancer cell
Volume	16
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2009.07.016
State	Published - Sep 8 2009

Keywords

CELLCYCLE

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2009.07.016

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@article{aea52348474949b3ac53ba6464a2cb29,

title = "FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt",

abstract = "Akt is a central regulator of cell growth. Its activity can be negatively regulated by the phosphatase PHLPP that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1). However, how PHLPP is targeted to Akt is not clear. Here we show that FKBP51 (FK506-binding protein 51) acts as a scaffolding protein for Akt and PHLPP and promotes dephosphorylation of Akt. Furthermore, FKBP51 is downregulated in pancreatic cancer tissue samples and several cancer cell lines. Decreased FKBP51 expression in cancer cells results in hyperphosphorylation of Akt and decreased cell death following genotoxic stress. Overall, our findings identify FKBP51 as a negative regulator of the Akt pathway, with potentially important implications for cancer etiology and response to chemotherapy.",

keywords = "CELLCYCLE",

author = "Huadong Pei and Liang Li and Fridley, {Brooke L.} and Jenkins, {Gregory D.} and Kalari, {Krishna R.} and Wilma Lingle and Gloria Petersen and Zhenkun Lou and Liewei Wang",

note = "Funding Information: This work was supported by the Richard Schultz Foundation (Z.L.), CA102701 (The Pancreatic Cancer Specialized Programs of Research Excellence) (Z.L., L.W., G.P., and W.L), R01CA138461 (Z.L., L.W.), K22CA130828 (L.W.), GM61388 (The Pharmacogenetics Research Network) (L.W., B.F., and R.K.), and the PhRMA Foundation “Center of Excellence in Clinical Pharmacology” Award (L.W.). ",

year = "2009",

month = sep,

day = "8",

doi = "10.1016/j.ccr.2009.07.016",

language = "English (US)",

volume = "16",

pages = "259--266",

journal = "Cancer cell",

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T1 - FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt

AU - Pei, Huadong

AU - Li, Liang

AU - Fridley, Brooke L.

AU - Jenkins, Gregory D.

AU - Kalari, Krishna R.

AU - Lingle, Wilma

AU - Petersen, Gloria

AU - Lou, Zhenkun

AU - Wang, Liewei

N1 - Funding Information: This work was supported by the Richard Schultz Foundation (Z.L.), CA102701 (The Pancreatic Cancer Specialized Programs of Research Excellence) (Z.L., L.W., G.P., and W.L), R01CA138461 (Z.L., L.W.), K22CA130828 (L.W.), GM61388 (The Pharmacogenetics Research Network) (L.W., B.F., and R.K.), and the PhRMA Foundation “Center of Excellence in Clinical Pharmacology” Award (L.W.).

PY - 2009/9/8

Y1 - 2009/9/8

N2 - Akt is a central regulator of cell growth. Its activity can be negatively regulated by the phosphatase PHLPP that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1). However, how PHLPP is targeted to Akt is not clear. Here we show that FKBP51 (FK506-binding protein 51) acts as a scaffolding protein for Akt and PHLPP and promotes dephosphorylation of Akt. Furthermore, FKBP51 is downregulated in pancreatic cancer tissue samples and several cancer cell lines. Decreased FKBP51 expression in cancer cells results in hyperphosphorylation of Akt and decreased cell death following genotoxic stress. Overall, our findings identify FKBP51 as a negative regulator of the Akt pathway, with potentially important implications for cancer etiology and response to chemotherapy.

AB - Akt is a central regulator of cell growth. Its activity can be negatively regulated by the phosphatase PHLPP that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1). However, how PHLPP is targeted to Akt is not clear. Here we show that FKBP51 (FK506-binding protein 51) acts as a scaffolding protein for Akt and PHLPP and promotes dephosphorylation of Akt. Furthermore, FKBP51 is downregulated in pancreatic cancer tissue samples and several cancer cell lines. Decreased FKBP51 expression in cancer cells results in hyperphosphorylation of Akt and decreased cell death following genotoxic stress. Overall, our findings identify FKBP51 as a negative regulator of the Akt pathway, with potentially important implications for cancer etiology and response to chemotherapy.

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JO - Cancer cell

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ER -

FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt

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