Rak Functions as a Tumor Suppressor by Regulating PTEN Protein Stability and Function

Eun Kyoung Yim; Guang Peng; Hui Dai; Ruozhen Hu; Kaiyi Li; Yiling Lu; Gordon B. Mills; Funda Meric-Bernstam; Bryan T. Hennessy; Rolf J. Craven; Shiaw Yih Lin

doi:10.1016/j.ccr.2009.02.012

Rak Functions as a Tumor Suppressor by Regulating PTEN Protein Stability and Function

Eun Kyoung Yim, Guang Peng, Hui Dai, Ruozhen Hu, Kaiyi Li, Yiling Lu, Gordon B. Mills, Funda Meric-Bernstam, Bryan T. Hennessy, Rolf J. Craven, Shiaw Yih Lin

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

159 Scopus citations

Abstract

Expression of the PTEN tumor suppressor is frequently lost in breast cancer in the absence of mutation or promoter methylation through as yet undetermined mechanisms. In this study, we demonstrate that the Rak tyrosine kinase physically interacts with PTEN and phosphorylates PTEN on Tyr336. Knockdown of Rak enhanced the binding of PTEN to its E3 ligase NEDD4-1 and promoted PTEN polyubiquitination, leading to PTEN protein degradation. Notably, ectopic expression of Rak effectively suppressed breast cancer cell proliferation, invasion, and colony formation in vitro and tumor growth in vivo. Furthermore, Rak knockdown was sufficient to transform normal mammary epithelial cells. Therefore, Rak acts as a bona fide tumor suppressor gene through the mechanism of regulating PTEN protein stability and function.

Original language	English
Pages (from-to)	304-314
Number of pages	11
Journal	Cancer Cell
Volume	15
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2009.02.012
State	Published - Apr 7 2009

Bibliographical note

Funding Information:
We thank Q. Yu of the Department of Systems Biology and M.-J. Kim of the Department of Pathology for technical assistance. We also thank Z. Lu of the Department of Neuro-Oncology for advice on the kinase assay and S. Siwko of the Department of Systems Biology and S. Deming of the Department of Scientific Publications at the M.D. Anderson Cancer Center for editorial assistance. This work was supported by NCI grant R01 CA120960 to S.-Y.L. and NIH grant 1K08-CA91895-01 to F.M.-B.

Funding

We thank Q. Yu of the Department of Systems Biology and M.-J. Kim of the Department of Pathology for technical assistance. We also thank Z. Lu of the Department of Neuro-Oncology for advice on the kinase assay and S. Siwko of the Department of Systems Biology and S. Deming of the Department of Scientific Publications at the M.D. Anderson Cancer Center for editorial assistance. This work was supported by NCI grant R01 CA120960 to S.-Y.L. and NIH grant 1K08-CA91895-01 to F.M.-B.

Funders	Funder number
National Institutes of Health (NIH)	1K08-CA91895-01
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	R01CA120960
National Childhood Cancer Registry – National Cancer Institute

Keywords

CELLCYCLE

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.2009.02.012

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title = "Rak Functions as a Tumor Suppressor by Regulating PTEN Protein Stability and Function",

abstract = "Expression of the PTEN tumor suppressor is frequently lost in breast cancer in the absence of mutation or promoter methylation through as yet undetermined mechanisms. In this study, we demonstrate that the Rak tyrosine kinase physically interacts with PTEN and phosphorylates PTEN on Tyr336. Knockdown of Rak enhanced the binding of PTEN to its E3 ligase NEDD4-1 and promoted PTEN polyubiquitination, leading to PTEN protein degradation. Notably, ectopic expression of Rak effectively suppressed breast cancer cell proliferation, invasion, and colony formation in vitro and tumor growth in vivo. Furthermore, Rak knockdown was sufficient to transform normal mammary epithelial cells. Therefore, Rak acts as a bona fide tumor suppressor gene through the mechanism of regulating PTEN protein stability and function.",

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author = "Yim, {Eun Kyoung} and Guang Peng and Hui Dai and Ruozhen Hu and Kaiyi Li and Yiling Lu and Mills, {Gordon B.} and Funda Meric-Bernstam and Hennessy, {Bryan T.} and Craven, {Rolf J.} and Lin, {Shiaw Yih}",

note = "Funding Information: We thank Q. Yu of the Department of Systems Biology and M.-J. Kim of the Department of Pathology for technical assistance. We also thank Z. Lu of the Department of Neuro-Oncology for advice on the kinase assay and S. Siwko of the Department of Systems Biology and S. Deming of the Department of Scientific Publications at the M.D. Anderson Cancer Center for editorial assistance. This work was supported by NCI grant R01 CA120960 to S.-Y.L. and NIH grant 1K08-CA91895-01 to F.M.-B. ",

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AU - Dai, Hui

AU - Hu, Ruozhen

AU - Li, Kaiyi

AU - Lu, Yiling

AU - Mills, Gordon B.

AU - Meric-Bernstam, Funda

AU - Hennessy, Bryan T.

AU - Craven, Rolf J.

AU - Lin, Shiaw Yih

N1 - Funding Information: We thank Q. Yu of the Department of Systems Biology and M.-J. Kim of the Department of Pathology for technical assistance. We also thank Z. Lu of the Department of Neuro-Oncology for advice on the kinase assay and S. Siwko of the Department of Systems Biology and S. Deming of the Department of Scientific Publications at the M.D. Anderson Cancer Center for editorial assistance. This work was supported by NCI grant R01 CA120960 to S.-Y.L. and NIH grant 1K08-CA91895-01 to F.M.-B.

PY - 2009/4/7

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N2 - Expression of the PTEN tumor suppressor is frequently lost in breast cancer in the absence of mutation or promoter methylation through as yet undetermined mechanisms. In this study, we demonstrate that the Rak tyrosine kinase physically interacts with PTEN and phosphorylates PTEN on Tyr336. Knockdown of Rak enhanced the binding of PTEN to its E3 ligase NEDD4-1 and promoted PTEN polyubiquitination, leading to PTEN protein degradation. Notably, ectopic expression of Rak effectively suppressed breast cancer cell proliferation, invasion, and colony formation in vitro and tumor growth in vivo. Furthermore, Rak knockdown was sufficient to transform normal mammary epithelial cells. Therefore, Rak acts as a bona fide tumor suppressor gene through the mechanism of regulating PTEN protein stability and function.

AB - Expression of the PTEN tumor suppressor is frequently lost in breast cancer in the absence of mutation or promoter methylation through as yet undetermined mechanisms. In this study, we demonstrate that the Rak tyrosine kinase physically interacts with PTEN and phosphorylates PTEN on Tyr336. Knockdown of Rak enhanced the binding of PTEN to its E3 ligase NEDD4-1 and promoted PTEN polyubiquitination, leading to PTEN protein degradation. Notably, ectopic expression of Rak effectively suppressed breast cancer cell proliferation, invasion, and colony formation in vitro and tumor growth in vivo. Furthermore, Rak knockdown was sufficient to transform normal mammary epithelial cells. Therefore, Rak acts as a bona fide tumor suppressor gene through the mechanism of regulating PTEN protein stability and function.

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Rak Functions as a Tumor Suppressor by Regulating PTEN Protein Stability and Function

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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