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

Producción científica: Article › revisión exhaustiva

166 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	304-314
Número de páginas	11
Publicación	Cancer Cell
Volumen	15
N.º	4
DOI	https://doi.org/10.1016/j.ccr.2009.02.012
Estado	Published - abr 7 2009

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
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

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Oncology
Cancer Research

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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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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.

KW - CELLCYCLE

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AN - SCOPUS:63249130027

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VL - 15

SP - 304

EP - 314

JO - Cancer Cell

JF - Cancer Cell

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

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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