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

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26 Scopus citations

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 (US)
Pages (from-to)1124-1138
Number of pages15
JournalMolecular and cellular biology
Volume32
Issue number6
DOIs
StatePublished - Mar 1 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Lin, H. H., Li, X., Chen, J. L., Sun, X., Cooper, F. N., Chen, Y. R., Zhang, W., Chung, Y., Li, A., Cheng, C. T., Yang, L., Deng, X. T., Liu, X., Yen, Y., Johnson, D. L., Shih, H. M., Yang, A., & Ann, D. K. (2012). Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia. Molecular and cellular biology, 32(6), 1124-1138. https://doi.org/10.1128/MCB.06053-11