Septins are a family of cytoskeletal GTP-binding proteins that assemble into membrane-associated hetero-oligomers and organize scaffolds for recruitment of cytosolic proteins or stabilization of membrane proteins. Septins have been implicated in a diverse range of cancers, including gastric cancer, but the underlying mechanisms remain unclear. The hypothesis tested here is that septins contribute to cancer by stabilizing the receptor tyrosine kinase ErbB2, an important target for cancer treatment. Septins and ErbB2 were highly over-expressed in gastric cancer cells. Immunoprecipitation followed by MS analysis identified ErbB2 as a septin-interacting protein. Knockdown of septin-2 or cell exposure to forchlorfenuron (FCF), a well-established inhibitor of septin oligomerization, decreased surface and total levels of ErbB2. These treatments had no effect on epidermal growth factor receptor (EGFR), emphasizing the specificity and functionality of the septin–ErbB2 interaction. The level of ubiquitylated ErbB2 at the plasma membrane was elevated in cells treated with FCF, which was accompanied by a decrease in co-localization of ErbB2 with septins at the membrane. Cathepsin B inhibitor, but not bafilomycin or lactacystin, prevented FCF-induced decrease in total ErbB2 by increasing accumulation of ubiquitylated ErbB2 in lysosomes. Therefore, septins protect ErbB2 from ubiquitylation, endocytosis and lysosomal degradation. The FCF-induced degradation pathway is distinct from and additive with the degradation induced by inhibiting ErbB2 chaperone Hsp90. These results identify septins as novel regulators of ErbB2 expression that contribute to the remarkable stabilization of the receptor at the plasma membrane of cancer cells and may provide a basis for the development of new ErbB2-targeting anti-cancer therapies.
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K-Ras4B membrane-anchored dimers in the cell. Dimerization can take place through helical (left) and beta-sheet (right) interfaces. The major (front) and minor (back) conformations are shown. For further details please see pp. 1719–1732. Image kindly provided by Ruth Nussinov. - PDF Icon PDF LinkFront Matter
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Research Article|
June 10 2016
Septin oligomerization regulates persistent expression of ErbB2/HER2 in gastric cancer cells
Elizabeth A. Marcus;
Elizabeth A. Marcus
*Department of Pediatrics, DGSOM at UCLA, Los Angeles, CA 90095, U.S.A.
†VA Greater Los Angeles Health Care System, Los Angeles, CA 90073, U.S.A.
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Elmira Tokhtaeva;
Elmira Tokhtaeva
†VA Greater Los Angeles Health Care System, Los Angeles, CA 90073, U.S.A.
‡Department of Physiology, DGSOM at UCLA, Los Angeles, CA 90095, U.S.A.
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Shahlo Turdikulova;
Shahlo Turdikulova
§Center for High Technology, Academy of Science, Tashkent 700174, Republic of Uzbekistan
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Joseph Capri;
Joseph Capri
║Pasarow Mass Spectrometry Laboratory, The NPI-Semel Institute, UCLA, Los Angeles, CA 90024, U.S.A.
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Julian P. Whitelegge;
Julian P. Whitelegge
║Pasarow Mass Spectrometry Laboratory, The NPI-Semel Institute, UCLA, Los Angeles, CA 90024, U.S.A.
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David R. Scott;
David R. Scott
†VA Greater Los Angeles Health Care System, Los Angeles, CA 90073, U.S.A.
‡Department of Physiology, DGSOM at UCLA, Los Angeles, CA 90095, U.S.A.
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George Sachs;
George Sachs
†VA Greater Los Angeles Health Care System, Los Angeles, CA 90073, U.S.A.
‡Department of Physiology, DGSOM at UCLA, Los Angeles, CA 90095, U.S.A.
¶Department of Medicine, DGSOM at UCLA, Los Angeles, CA 90095, U.S.A.
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Fedor Berditchevski;
Fedor Berditchevski
**School of Cancer Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, U.K.
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Olga Vagin
Olga Vagin
1
†VA Greater Los Angeles Health Care System, Los Angeles, CA 90073, U.S.A.
‡Department of Physiology, DGSOM at UCLA, Los Angeles, CA 90095, U.S.A.
1To whom correspondence should be addressed (email olgav@ucla.edu).
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Publisher: Portland Press Ltd
Received:
December 03 2015
Revision Received:
April 04 2016
Accepted:
April 05 2016
Accepted Manuscript online:
April 05 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (12): 1703–1718.
Article history
Received:
December 03 2015
Revision Received:
April 04 2016
Accepted:
April 05 2016
Accepted Manuscript online:
April 05 2016
Citation
Elizabeth A. Marcus, Elmira Tokhtaeva, Shahlo Turdikulova, Joseph Capri, Julian P. Whitelegge, David R. Scott, George Sachs, Fedor Berditchevski, Olga Vagin; Septin oligomerization regulates persistent expression of ErbB2/HER2 in gastric cancer cells. Biochem J 15 June 2016; 473 (12): 1703–1718. doi: https://doi.org/10.1042/BCJ20160203
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