Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia

H. Helen Lin, Xu Li, Jo Lin Chen, Xiuzhu Sun, Fariba Norouziyan Cooper, Yun Ru Chen, Wenyu Zhang, Yiyin Chung, Angela Li, Chun Ting Cheng, Lixin Yang, Xu Tao Deng, Xiyong Liu, Yun Yen, Deborah L. Johnson, Hsiu Ming Shih, Austin Yang, David K. Ann

Research output: Contribution to journalArticle

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Abstract

VPS4B, an AAA ATPase (ATPase associated with various cellular activities), participates in vesicular trafficking and autophagosome maturation in mammalian cells. In solid tumors, hypoxia is a common feature and an indicator of poor treatment outcome. Our studies demonstrate that exogenous or endogenous (assessed with anchorage-independent three-dimensional multicellular spheroid culture) hypoxia induces VPS4B downregulation by the ubiquitin-proteasome system. Inhibition of VPS4B function by short hairpin VPS4B (sh-VPS4B) or expression of dominant negative VPS4B(E235Q) promotes anchorageindependent breast cancer cell growth and resistance to gefitinib, U0126, and genotoxicity. Biochemically, hyperactivation of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase essential for cell proliferation and survival, accompanied by increased EGFR accumulation and altered intracellular compartmentalization, is observed in cells with compromised VPS4B. Furthermore, enhanced FOS/JUN induction and AP-1 promoter activation are noted in EGF-treated cells with VPS4B knockdown. However, VPS4B depletion does not affect EGFRvIII stability or its associated signaling. An inverse correlation between VPS4B expression and EGFR abundance is observed in breast tumors, and high-grade or recurrent breast carcinomas exhibit lower VPS4B expression. Together, our findings highlight a potentially critical role of VPS4B downregulation or chronichypoxia- induced VPS4B degradation in promoting tumor progression, unveiling a nongenomic mechanism for EGFR overproduction in human breast cancer.

Original languageEnglish
Pages (from-to)1124-1138
Number of pages15
JournalMolecular and Cellular Biology
Volume32
Issue number6
DOIs
Publication statusPublished - Mar 1 2012
Externally publishedYes

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Epidermal Growth Factor Receptor
Adenosine Triphosphatases
Breast Neoplasms
Down-Regulation
Cellular Spheroids
Transcription Factor AP-1
Receptor Protein-Tyrosine Kinases
Proteasome Endopeptidase Complex
Ubiquitin
Epidermal Growth Factor
Cell Survival
Cell Proliferation
Hypoxia
Growth
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia. / Lin, H. Helen; Li, Xu; Chen, Jo Lin; Sun, Xiuzhu; Cooper, Fariba Norouziyan; Chen, Yun Ru; Zhang, Wenyu; Chung, Yiyin; Li, Angela; Cheng, Chun Ting; Yang, Lixin; Deng, Xu Tao; Liu, Xiyong; Yen, Yun; Johnson, Deborah L.; Shih, Hsiu Ming; Yang, Austin; Ann, David K.

In: Molecular and Cellular Biology, Vol. 32, No. 6, 01.03.2012, p. 1124-1138.

Research output: Contribution to journalArticle

Lin, HH, Li, X, Chen, JL, Sun, X, Cooper, FN, Chen, YR, Zhang, W, Chung, Y, Li, A, Cheng, CT, Yang, L, Deng, XT, Liu, X, Yen, Y, Johnson, DL, Shih, HM, Yang, A & Ann, DK 2012, 'Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia', Molecular and Cellular Biology, vol. 32, no. 6, pp. 1124-1138. https://doi.org/10.1128/MCB.06053-11
Lin, H. Helen ; Li, Xu ; Chen, Jo Lin ; Sun, Xiuzhu ; Cooper, Fariba Norouziyan ; Chen, Yun Ru ; Zhang, Wenyu ; Chung, Yiyin ; Li, Angela ; Cheng, Chun Ting ; Yang, Lixin ; Deng, Xu Tao ; Liu, Xiyong ; Yen, Yun ; Johnson, Deborah L. ; Shih, Hsiu Ming ; Yang, Austin ; Ann, David K. / Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia. In: Molecular and Cellular Biology. 2012 ; Vol. 32, No. 6. pp. 1124-1138.
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AU - Lin, H. Helen

AU - Li, Xu

AU - Chen, Jo Lin

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AU - Cooper, Fariba Norouziyan

AU - Chen, Yun Ru

AU - Zhang, Wenyu

AU - Chung, Yiyin

AU - Li, Angela

AU - Cheng, Chun Ting

AU - Yang, Lixin

AU - Deng, Xu Tao

AU - Liu, Xiyong

AU - Yen, Yun

AU - Johnson, Deborah L.

AU - Shih, Hsiu Ming

AU - Yang, Austin

AU - Ann, David K.

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N2 - VPS4B, an AAA ATPase (ATPase associated with various cellular activities), participates in vesicular trafficking and autophagosome maturation in mammalian cells. In solid tumors, hypoxia is a common feature and an indicator of poor treatment outcome. Our studies demonstrate that exogenous or endogenous (assessed with anchorage-independent three-dimensional multicellular spheroid culture) hypoxia induces VPS4B downregulation by the ubiquitin-proteasome system. Inhibition of VPS4B function by short hairpin VPS4B (sh-VPS4B) or expression of dominant negative VPS4B(E235Q) promotes anchorageindependent breast cancer cell growth and resistance to gefitinib, U0126, and genotoxicity. Biochemically, hyperactivation of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase essential for cell proliferation and survival, accompanied by increased EGFR accumulation and altered intracellular compartmentalization, is observed in cells with compromised VPS4B. Furthermore, enhanced FOS/JUN induction and AP-1 promoter activation are noted in EGF-treated cells with VPS4B knockdown. However, VPS4B depletion does not affect EGFRvIII stability or its associated signaling. An inverse correlation between VPS4B expression and EGFR abundance is observed in breast tumors, and high-grade or recurrent breast carcinomas exhibit lower VPS4B expression. Together, our findings highlight a potentially critical role of VPS4B downregulation or chronichypoxia- induced VPS4B degradation in promoting tumor progression, unveiling a nongenomic mechanism for EGFR overproduction in human breast cancer.

AB - VPS4B, an AAA ATPase (ATPase associated with various cellular activities), participates in vesicular trafficking and autophagosome maturation in mammalian cells. In solid tumors, hypoxia is a common feature and an indicator of poor treatment outcome. Our studies demonstrate that exogenous or endogenous (assessed with anchorage-independent three-dimensional multicellular spheroid culture) hypoxia induces VPS4B downregulation by the ubiquitin-proteasome system. Inhibition of VPS4B function by short hairpin VPS4B (sh-VPS4B) or expression of dominant negative VPS4B(E235Q) promotes anchorageindependent breast cancer cell growth and resistance to gefitinib, U0126, and genotoxicity. Biochemically, hyperactivation of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase essential for cell proliferation and survival, accompanied by increased EGFR accumulation and altered intracellular compartmentalization, is observed in cells with compromised VPS4B. Furthermore, enhanced FOS/JUN induction and AP-1 promoter activation are noted in EGF-treated cells with VPS4B knockdown. However, VPS4B depletion does not affect EGFRvIII stability or its associated signaling. An inverse correlation between VPS4B expression and EGFR abundance is observed in breast tumors, and high-grade or recurrent breast carcinomas exhibit lower VPS4B expression. Together, our findings highlight a potentially critical role of VPS4B downregulation or chronichypoxia- induced VPS4B degradation in promoting tumor progression, unveiling a nongenomic mechanism for EGFR overproduction in human breast cancer.

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